bluuebunny/crossref_metadata_2025 huggingface dataset:
Morbidity associated to advanced gastric cancer and its impact on overall survival.
Authors: Meneses Medina Mónica Isabel , Valenzuela Ana Karen , Hernandez-Felix Jorge Humberto , Verduzco-Aguirre Haydee Cristina , Camargo Vanessa Rosas , Cortez Dominguez Edwin Ulises , Anaya Sánchez Luis Guillermo , Noguez-Ramos Alejandro , Huitzil Melendez Fidel David
Published: February 2020

327

Background: Advanced gastric cancer (GC) is a disease with high morbidity and poor prognosis. We hypothesize that different sites of metastasis have different impact in terms of symptoms and complications. We sought to evaluate if site specific morbidity in our patients impacted treatment and survival. Methods: Medical records from patients with advanced GC treated from Jan 2005 to Dec 2015 were retrospectively reviewed. Morbidity was defined as having any symptom by metastases in a specific site. OS was estimated by Kaplan Meier method and compared by Log-rank test. P value < 0.05 was considered significant. Results: We included 180 consecutive patients, median age at diagnosis was 56 years (21-90), 55% were women. Most common sites of metastases were: peritoneum 76.1%, non-regional lymph nodes 38.9%, liver 22.8%, lung 26.7%, bone 9.4% and ovary 12.8%. Regarding morbidity, at diagnosis 68% of patients presented morbidity by the primary tumor: obstruction 56%, bleeding 27%, obstruction and bleeding 3%, other 14%. Disease by peritoneum caused morbidity in 30%, by lung in 8%, by ovarian in 4.4%, by lymph nodes in 3.3%, and by other sites in 5.6% of patients. OS in the global cohort was: 3.53 months (2.2 to 4.8), nevertheless by univariate analysis we found that OS was affected by morbidity at some sites as it is show in table. More patients with peritoneal morbidity could not receive treatment vs those without peritoneal morbidity (p = 0.042). Conclusions: We found that morbidity in peritoneum, lung and ovary adversely affected prognosis of patients with advanced GC. Moreover, peritoneal morbidity preclude patients from receiving oncological treatment.

[Table: see text]
Patterns of gastric cancer metastasis within the United States.
Authors: Sirody Joseph , Kaji Amy H. , Hari Danielle M. , Chen Kathryn Tzung-Kai
Published: February 2020

329

Background: There are few reports on the epidemiology of gastric cancer metastasis, although outcomes are known to be uniformly poor. Here we describe the patterns of gastric cancer metastasis and treatment in the United States (US). Methods: Patients with gastric adenocarcinoma histologies were identified in the National Cancer Database (NCDB) from 2004-2016. We describe univariate associations between different sites of metastasis and clinicopathologic characteristics and treatment modalities, using the chi-square and Kruskal-Wallis tests. Kaplan Meier curves were constructed for the estimation of overall survival (OS) by metastatic site. Results: Due to changes in the coding of metastatic disease, we were limited to the year 2016 for evaluation of patterns of disease. Twenty-six percent (n = 1228) of gastric cancer patients presented with liver metastases, 20% (n = 941) with distant nodes, 43% (n = 2028) with other distant site metastases (including peritoneum), and the rest to bone, brain or lung. On univariate analysis, when compared to liver metastases, other distant site metastases were significantly more likely to arise from an antral primary site (28% v. 16%); to be of Hispanic origin (16% v. 7%); female (42% v. 29%); associated with signet ring histology (34% v. 6%); lymphovascular invasion (LVI) (58% v. 27%); and tumor grade III/IV (85% vs. 60%) (p < 0.0001 for all). There were no significant differences in how patients with metastatic disease were treated in terms of systemic therapy. With regard to OS, due to how metastatic sites were coded prior to 2016, it was not possible to compare peritoneal metastases against other sites; however, patients with distant nodal disease had improved median overall survival compared to those with any other metastatic site (7.9 v. 5.2 months, p < 0.0001). Conclusions: The majority of US patients with metastatic gastric cancer present with presumed peritoneal disease. Predictive factors for peritoneal metastases vs. liver metastases included adverse prognostic features, including signet ring histology, higher tumor grades, and LVI. Although it was not possible to compare OS of peritoneal disease against other sites, continued follow up is needed, as this may impact future staging.
Safety, pharmacokinetics, and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer.
Authors: Gong Jifang , Fang Jianmin , Shen Lin
Published: February 2020

334

Background: HER2 overexpression is common in many malignancies and contributes to tumor growth. Unlike the varied options of anti-HER2 target therapies for breast cancer, there is a huge unmet medical need for HER2 overexpressing non-breast solid tumor (NBST) such as gastric cancer and urothelial cancer. Therefore, we conducted the first study of RC48-ADC, a novel humanized anti-HER2 antibody conjugate, in NBST. Methods: This was an open-label, dose-escalation and expansion study in patients with HER2-overexpression (IHC 2+ and 3+) advanced solid cancers after failure of standard treatment. The dose escalation consisted of accelerated (0.1 and 0.5 mg/kg) and “3+3” titrations (1.0, 2.0, 2.5 and 3.0 mg/kg). In dose expansion stage, patients were given RC48-ADC at 2.0 mg/kg, Q2W. Results: As of Aug 20, 2019, 57 patients (including 47 with gastric cancer and 4 with urothelial cancer) were treated at 0.1 (1 patient), 0.5 (1 patient), 1.0 (3 patients), 2.0 (6 patients in dose escalation and 32 patients in dose expansion), 2.5 (11 patients), and 3.0 mg/kg (3 patients), respectively. Most of them were Stage IV (91.2%) or with metastasis (96.5%). DLT was observed in 1, 2, and 1 patient at 2.0, 2.5, and 3.0 mg/kg, respectively. The MTD was 2.5 mg/kg. Most commonly reported TRAEs were WBC count decreased (66.7%), fatigue (56.1%), neutrophil count decreased (54.4%) and hemoglobin decreased (52.6%). Grade 3/4 TRAEs were reported in 28 patients (49.1%). Confirmed ORR was 21.1% (8/38) for 2.0 mg/kg, and 17.5% (10/57) for all patients. DCR was 52.6% and 49.1%, respectively. PFS was 3.6 months (95% CI: 4.1, 11.3) for 2.0 mg/kg. Subgroup ORR was 20.7% (6/29) at 2.0 mg/kg and 18.2% (2/11) at 2.5 mg/kg for gastric cancer, and 50.0% (2/4) for urothelial cancer. Conclusions: RC48-ADC demonstrated a good safety profile and promising anti-tumor activity in the late stage solid tumor including gastric cancer and urothelial cancer. Response and PFS benefits were clinical meaningful at 2.0 mg/kg and 2.5 mg/kg. Phase 2 pivotal study (NCT03556345) in gastric cancer is ongoing. Clinical trial information: NCT02881190.
Per oral vitamin B12 replacement therapy after gastrectomy and its optimal dose (retrospective study) and our protocol of a prospective clinical trial.
Authors: Rino Yasushi , Aoyama Toru , Yukawa Norio , Cho Haruhiko , Oshima Takashi , Yamada Takanobu , Atsumi Yosuke , Hara Kentaro , Numata Masakatsu , Kazama Keisuke , Tamagawa Hiroshi , Sato Tsutomu , Yoshikawa Takaki
Published: February 2020

338

Background: Postgastrectomy vitamin B12 deficiency is common metabolic sequel and worsens the quality of life of gastric cancer survivors. Recently, oral vitamin B12 replacement is reported. Therefore, we investigated retrospectively the efficacy of oral vitamin B12 replacement for gastric cancer patients with vitamin B12 deficiency after total gastrectomy. Methods: We reviewed 73 patients with gastric cancer who underwent total gastrectomy and were treated vitamin B12 replacement. Patients were consisted of 56 males and 17 females and median age was 70 y/o. We investigated initial treatment of vitamin B12 replacement and improvement of vitamin B12 deficiency. Results: Initial treatment of vitamin B12 replacements were intramuscular injection for 42 patients, per oral replacement for 28 patients and intravenous injection for 3 patients. Finally, all patients were treated with per oral replacement and the serum vitamin B12 levels became within normal range. Final vitamin B12 doses of replacement therapy were 500 µg of 20 out of 73 pts, respectively. Conclusions: Vitamin B12 replacement therapy should be necessary and continued. According to our results, one vitamin B12 tablet a day is enough. The vitamin B12 deficiency symptoms could be prevented. 500 micrograms vitamin B12 replacement orally is maybe effective and necessary. Our prospective clinical protocol (UMIN000030727): In this study, an oral vitamin B12 preparation (1500 μg/day, administered daily) was set as the control treatment, and a specific clinical trial was started to determine whether 500 μg/day daily administration would be sufficient for replacement therapy. Clinical trial information: UMIN000030727.
An economic evaluation of palliation of dysphagia in esophageal cancer: Analysis of the TROG 03.01/NCIC ES.2 phase III study in advanced esophageal cancer in patients treated with radiotherapy versus chemoradiotherapy.
Authors: Penniment Michael Gordon , De Ieso Paolo , Wong Rebecca , Afzali Hossein
Published: February 2020

340

Background: In advanced oesophageal cancer (OC), 90% of patients have dysphagia as a principal symptom. The randomised TROG 03.01 trial reported no significant overall survival or dysphagia relief difference between 15 fractions (#) radiotherapy alone (RT) or RT plus chemotherapy (CRT) Future studies may consider RT hypofractionation, different chemotherapy, esophageal stenting, and best supportive care. Comparing costs and outcomes, economic evaluation often informs public funding decisions in countries such as Australia and the UK. The objective of this analysis was to derive baseline cost and outcome for further studies. Methods: Given equal outcomes (non-inferiority) between treatment arms, cost-minimisation analysis (CMA) was used to evaluate cost-effectiveness, cost a deciding factor if no other benefit was predicted. We explored 15 and 10 # courses used in TROG 03.01 and alternatives, 1 or 5 # Study design and uncertainty analyses were provided. Sub-analysis assessed salvage therapy for local and systemic progression. The EQ-5D (and SF-12) was used to determine utility values to estimate Quality-Adjusted Life years (QALYs) for evaluation. Results: From a health system perspective, costs and outcomes of RT were estimated at $4,700 AUD (15 # course). If, compared with RT alone, an alternative option is more costly but more effective, then a cost-utility analysis (CUA) is preferred economic evaluation. Intervention and in/outpatient costs, initial phase and post treatment were considered for stent insertion and alternative chemotherapy regimens. Alternatively, autocontoured CT planning and machine learning were modelled to reduce RT planning cost (est. $650/p). Total cost for 5 # is $3200 could be further reduced through process efficiency savings using CMA approach. Conclusions: The value of palliative approaches in common malignancies is difficult to assess. This study uses economic analysis to guide paying authority decisions. RT can be simplified from the TROG 03.01 approach to lessen cost and simplify treatment. The clinical efficiency of 1 or 5 # should be evaluated.
Perioperative docetaxel, oxaliplatin, and capecitabine (DOX) in resectable adenocarcinomas of lower esophagus, esophagogastric junction, and stomach.
Authors: Valame Shaunak , Panda Dipanjan , Zaidi Shuaib , Garg Praveen , Razvi Syed Asim , Singhal Manish Kumar , Das Pratap K. , Baweja Pankaj , Patowary Jayanta
Published: February 2020

349

Background: In a real-world scenario, Fluorouracil-based triplet combination chemotherapies have limited feasibility with regards to toxicity, need for central venous access, and hospitalization. The primary objective of this study was to assess pathological tumor regression to Capecitabine-based triplet regimes, with the additional possible benefit of overcoming the aforementioned barriers. Methods: This Single-Arm, Prospective study investigated the primary outcome of histopathologic regression to perioperative Docetaxel, Oxaliplatin, and Capecitabine (DOX) combination regime in histologically confirmed resectable Esophageal, Esophagogastric Junction, and Gastric Adenocarcinomas. Three preoperative and 3 postoperative cycles of Docetaxel 60mg/m2 plus Oxaliplatin 100mg/m2 on Day 1, with Capecitabine 500mg/m2 twice daily from Day 1 to Day 21 were administered, with cycles repeating every 21 days. Histopathologic regression was assessed by Modified Ryan’s Schema on surgical specimen. The study had an 80% power (two-sided significance of 0.05) to detect a 20% pathological complete response. Secondary endpoints were Overall Survival, Progression-Free Survival, and Toxicity analysis. Results: Between June 2017 to May 2019, 28 patients (median age 54.5 years [Range 33 – 82]; Male 78.6%; ECOG PS 1/2 = 42.9%/57.1%) were enrolled in the study of which 92.9% completed preoperative chemotherapy. Of the 20 patients operated upon, 100% were R0 resections. Pathological complete response was observed in 20% (4/20). Ninety percent of the operated patients completed the postoperative treatment. The most common grade ≥3 toxicities were Palmar-Plantar Erythrodysesthesia (10.7%), Fatigue (10.7%), and Diarrhoea (7.1%). Conclusions: Perioperative DOX met its primary endpoint of 20% pathologic complete regression with a favourable toxicity profile and was feasible to administer in resectable Esophageal, Esophagogastric Junction, and Gastric Adenocarcinomas. This regimen deserves further evaluation in larger phase III trials.
Personalized ANtibodies for GastroEsophageal Adenocarcinoma (PANGEA): Primary efficacy analysis of the phase II platform trial (NCT02213289).
Authors: Catenacci Daniel V.T. , Lomnicki Samantha , Chase Leah , Peterson Bryan , Moore Kelly , Markevicius Ugne , Alpert Lindsay , Setia Namrata , Hart John , Liao Chih-Yi , Siddiqui Uzma , Turaga Kiran , Posner Mitchell C. , Kipping-Johnson Kristen , Narula Sunil , Rampurwala Murtuza M. , Ji Yuan , Karrison Theodore , Polite Blase N. , Kindler Hedy L.
Published: February 2020

356

Background: 1-yr OS is ~40% for HER2- & ~55% for HER2+ advanced (aGEA). Targeted therapies (tx) have had limited benefit due to molecular heterogeneity. Methods: This phase 2a study of a personalized tx strategy (PTS) enrolled newly diagnosed aGEA pts who then received up to 3 cytotoxic (cx) lines: first line (1L) 5FU + oxaliplatin, 2L 5FU + irinotecan & 3L 5FU + docetaxel. Baseline biomarker profiling (BP) was mandated on primary & metastatic tumors (PT/MT) & progressive disease points (PD1, PD2). Assigned antibody (AN) was added to cx by a predefined prioritized tx algorithm (PTA) (Table) based on the MT BP. At PD1, pts went to 2L cx + initial AN. Upon results of PD1 BP, pts changed AN only if BP evolved per PTA. The same was done at PD2. If AN was unavailable (MET/FGFR2), these pts were tx’d with cx alone (not ITT). The 10 endpt was 1-yr OS of the PTS. Assuming historical 50% 1-yr OS for all aGEA pts, 68 pts tx’d per protocol PTS provided 80% power to detect an HR=0.67, corresponding to a 1-yr OS rate of 63% (under exponential survival), using a 1-sided test at the 0.10 alpha level. 20 endpts: safety, feasibility, PT/MT BP discordance at baseline & over tx line, & OS/PFS/ORR by tx line & BP group. Results: Between 6/2015-5/2019, 80 consecutive pts enrolled at 3 sites: ECOG PS 0-2 40/33/7; Male 80%; median age 60, range 28-81, peritoneal disease 36%. AN assigned by PTA at 1L & 1-yr OS are shown (Table). PT/MT discordance was 37%. Of 68 pts treated by PTS ITT, the 1-yr OS was 69.4% (p<0.001). The mOS was 16.4m [95%CI 13.8-20.8]. Any grade >3 tox thru all 3 tx lines was seen in 32% of pts. 20 analyses will be presented. Conclusions: PANGEA was feasible & met its 10 efficacy objective with observed 1-yr OS of 69.4%, meriting a randomized study. Clinical trial information: NCT02213289 . U.S. National Institutes of Health.[Table: see text]
How do social determinants of health impact timeliness of chemotherapy and survival in patients with metastatic colon cancer? A 12-year study.
Authors: Jayakrishnan Thejus Thayyil , Bakalov Veli , Chahine Zena , Finley Gene Grant , Monga Dulabh K. , Wegner Rodney E.
Published: February 2020

36

Background: Studies have demonstrated disparities in health care driven by socioeconomic factors. Patients with metastatic cancer represent the most vulnerable group of cancer patients. We hypothesized that these factors impact timeliness to chemotherapy in patients with metastatic colon cancer and their treatment outcomes. Methods: We queried the National Cancer Database (NCDB) for patients with metastatic colon cancer (AJCC pathologic stage4) diagnosed from 2004-2016. We selected patients treated with chemotherapy as first line treatment within 90 days of diagnosis. Time to initiation (TTI) was defined as time in days (d) from diagnosis of cancer to initiation of systemic chemotherapy and survival was measured in terms of months (m) from the day of diagnosis. Stepwise negative binomial regression and Cox proportional hazard models were used for analysis. Results: We identified 11,764 patients meeting the eligibility criteria. Median age was 62 (range 18-90) years and included 51% males. Median TTI was 9d (range 1-89) and median overall survival was 24.3m. TTI was significantly associated with race - Caucasian 26.4d (95% CI 25.6-27.1) vs. African American 28.9d (26.9-31.0) p-value=0.021, Median income - ≥ $63,000 23.5d (95% CI 22.4 – 24.5) vs.< $38,000 29.2d (27.3 – 31.0) p-value < 0.0001, Facility type – Community cancer center 23.6d (95% CI 21.6-25.6) vs. Academic/research program 26.5d (95% CI 25.5 – 27.4) p-value=0.014. Factors impacting survival in a multivariate model included time to chemotherapy initiation – 24.7m with TTI ≤ 9d vs. 23.8m with TTI > 9d (p-value <0.0001), type of facility – Academic/research program 26.4m vs. community cancer center 21.3 (p-value <0.0001), age (p-value <0.001), comorbidities (p-value <0.0001) and site of primary. Conclusions: Patients with metastatic cancer are not free from disparities driven by social determinants of health that impact their outcomes. The findings suggest that further studies to identify barriers to healthcare access and continued efforts to improve them are warranted.
A phase I/II multisite study of nivolumab and carboplatin/paclitaxel with radiation therapy (RT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC).
Authors: Wu Jennifer J. , Atkinson Emily Catherine , Leichman Lawrence P. , Patel Hitendra , Iqbal Syma , Du Kevin Lee , Bizekis Costas , Goldberg Judith D. , Thomas Charles R. , Cohen Deirdre Jill , Becker Daniel Jacob , Siolas Despina , Beri Nina , Oberstein Paul Eliezer , Ku Geoffrey Yuyat
Published: February 2020

372

Background: Preoperative chemoRT is a standard-of-care as shown in the CROSS trial ( N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit ( J Clin Oncol 2005;23:2310-2317, J Clin Oncol 2007;25:1160-1168). Nivolumab has activity in advanced ESCC ( Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes. Methods: This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is “unacceptable toxicity” at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W ×2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W ×3; if cCR, pt has an option of no surgery but receives nivolumab q2W ×3. Results: From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred. Conclusions: ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia
Laparoscopic versus open total gastrectomy for clinical stage I gastric cancer: Morbidity and mortality results from a prospective randomized multicenter controlled trial (CLASS02).
Authors: Liu Fenglin , Huang Changming , Xu Zekuan , Su Xiangqian , Zhao Gang , Ye Jianxin , Du Xiaohui , Huang Hua , Hu Jiankun , Li Guoxin , Yu Peiwu , Li Yong , Suo Jian , Zhao Naiqing , Zhang Wei , Li Haojie , He Hongyong , Sun Yihong ,   Chinese Laparoscopic Gastrointestinal Surgery Study Group
Published: February 2020

378

Background: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains lack of clinical evidence. The aim of this study was to compare the safety of LTG for clinical stage I gastric cancer with the conventional open total gastrectomy (OTG). Methods: From January 2017 to September 2018, a total of 227 patients with clinical stage T1N0-1M0/T2N0M0 gastric cancer were enrolled in this clinical trial and randomly assigned to Laparoscopic Gastrectomy group (LG, n=113) or Open Gastrectomy group (OG, n=114). The morbidity and mortality within 30 days following surgery, the recovery course, and the postoperative hospital stay between LG group (n=105) and OG group (n=109) were compared. Clavien-Dindo classification system was used to stratify surgical complications. Results: The overall morbidity rate was not significantly different in each group (LG group: 19.05%; OG group: 20.18%; Rate difference [RD]: -1.14%, 95%CI, -11.75%-9.58%). Intraoperative complications occurred in 3 (2.86%) patients in LG group and 4 (3.67%) patients in OG group (RD: -0.81%, 95%CI, -6.52%-4.85%). In addition, there was no significant difference in the overall postoperative complication rate of 18.10% in LG group and 17.43% in OG group (RD: 0.66%, 95%CI, -9.61%-11.01%). Each subtypes of postoperative complication were not significantly different between groups. One patient in LG group died of intra-abdominal bleeding from splenic artery, and there was no significant difference in mortality between LG group and OG group (RD: 0.95%, 95%CI, -2.54%-5.20%). The distribution of severity was similar between the two groups. Conclusions: Experienced surgeons can safely perform LTG with lymphadenectomy for clinical stage I gastric cancer. Clinical trial information: NCT03007550.
Immune-related adverse events and neutrophil-to-lymphocyte ratio are possible predictive factors for gastric cancer treated with nivolumab.
Authors: Eda Hirotugu , Tozawa Katsuyuki , Nakamura Kumiko , Kondo Takashi , Tomita Toshihiko , Oshima Tadayuki , Fukui Hirokazu , Miwa Hiroto
Published: February 2020

385

Background: The Immune-related adverse events (irAEs) and neutrophil-to-lymphocyte ratio (NLR) are effective as a predictive factor for lung cancer treated with nivolumab The objective of this study was to determine the effectiveness of irAEs and NLR for patients with advanced gastric cancer (AGC) treated with nivolumab. Methods: This was a retrospective study of patients with AGC treated with nivolumab from October 2017 to August 2019. The NLRs were calculated before the first cycle. Results: Forty patients were enrolled (males 29, females 11) with a median age of 65 years. The overall response rate was 12.5%. The median PFS was 4.2 months (range, 0.5 - 21). Stratified with high NLR (≥5) and low NLR ( < 5), the median PFS was shorter in the high NLR arm (1.1 vs. 5.1 months; p = 0.0003). irAEs were observed in 5 of the 40 study patients (12.5%), including 1 patients (20%) with such events of grade 3 or 4, and 1 patient requiring systemic corticosteroid therapy. Median PFS was 6.5 months (95% CI, 4.4 to not reached [NR]) and 3.9 months (95% CI, 3.0 to 7.5) (P = .09) for patients with or without irAEs, respectively. Conclusions: NLR may be an effective prognostic factor in patients with AGC treated with nivolumab. Development of irAEs was associated with survival outcome of nivolumab treatment in patients with AGC. Further studies are needed to confirm our findings.
Concurrent versus sequential neoadjuvant chemoradiation therapy for esophageal and gastroesophageal junction adenocarcinoma.
Authors: Torphy Robert J. , Ho Felix , Friedman Chloe , Leong Stephen , Wani Sachin , Scott Christopher D. , Weyant Michael J. , Meguid Robert A. , Gleisner Ana , Goodman Karyn A. , McCarter Martin D.
Published: February 2020

395

Background: Neoadjuvant therapy is the standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma, with most patients receiving neoadjuvant chemoradiation (CRT). CRT can be delivered concurrently or sequentially after induction chemotherapy. The purpose of this study was to evaluate pathologic complete response (pCR) and overall survival (OS) among patients who received concurrent versus sequential CRT in the National Cancer Database (NCDB). Methods: Patients who received neoadjuvant CRT and underwent curative intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006-2015 were included. Patients with clinical T4 or metastatic disease were excluded. Concurrent CRT was defined as radiation treatment starting within 6 weeks of chemotherapy start. Sequential CRT was defined as radiation treatment starting greater than 6 weeks after chemotherapy start. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. Results: 12,460 patients met inclusion criteria. 11,880 (95%) patients received concurrent CRT and 580 (5%) patients received sequential CRT. Patients who received sequential CRT were significantly younger (mean age: 60.7 vs 62.2 years), had higher clinical nodal stage (N2-3: 14.7% vs 10.1%), and were more often treated at academic/research hospitals (67.1 vs 55.5) (all p≤0.001). pCR was achieved in 16.2% of patients who received sequential CRT and in 14.0% of patients who received concurrent CRT (p = 0.131). Following propensity weighting, OS was significantly improved among patients who received sequential versus concurrent CRT (HR 0.82; 95% CI 0.74-0.92; p < 0.001) with a median OS for the sequential cohort of 41.4 months versus 29.4 months for those who received concurrent CRT. Conclusions: In this retrospective study from a large national database of patients who received neoadjuvant CRT for esophageal and GEJ adenocarcinoma, sequential CRT is associated with a significant OS benefit. These results merit consideration of a well powered prospective multi-institutional randomized clinical trial to further evaluate this observed difference.
Safety of perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: An interim safety analysis of the DANTE, a randomized, open-label phase II trial of the German Gastric Group at the AIO and the SAKK.
Authors: Al-Batran Salah-Eddin , Lorenzen Sylvie , Schenk Michael , Thuss-Patience Peter C. , Goekkurt Eray , Hofheinz Ralf , Kretzschmar Albrecht , Bolling Claus , Angermeier Stefan , Wicki Andreas , Siebenhuener Alexander Rheinhard , Eigendorff Ekkehard , Pink Christin , Ettrich Thomas Jens , Schmalenberg Harald , Waberer Lisa , Talbot Jonathan , Pauligk Claudia , Goetze Thorsten Oliver , Homann Nils
Published: February 2020

398

Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sept 2018; by September 2019, a total of 122 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: perioperative atezolizumab plus FLOT is feasible and safe. The study continued recruitment. Clinical trial information: NCT03421288.
Implications of postoperative complications on survival after cytoreductive surgery and HIPEC: A multi-institutional analysis of the United States HIPEC Collaborative.
Authors: Gamboa Adriana C. , Lee Rachel M. , Turgeon Michael K. , Ahmed Ahmed , Grotz Travis Edward , Fournier Keith F. , Dineen Sean Patrick , Veerapong Jula , Clarke Callisia , Mogal Harveshp , Patel Sameer H. , Lambert Laura A. , Abbott Daniel Erik , Raoof Mustafa , Johnston Fabian McCartney , Cloyd Jordan , Maithel Shishir K. , Staley Charles A.
Published: February 2020

40

Background: Postoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on the survival of patients with appendiceal or colorectal cancer after cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) is unknown. Methods: US HIPEC Collaborative (2000-17) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. Analysis was stratified by non-invasive appendiceal neoplasm vs invasive appendiceal/colorectal adenocarcinoma. POCs were grouped into infectious, cardiopulmonary, thromboembolic and intestinal dysmotility. Primary outcomes were 3-yr overall survival (OS) and recurrence-free survival (RFS). Results: Of 1304 pts, median age was 55 yrs, 41% were male (n = 537), 33% had non-invasive appendiceal (n = 426) and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the non-invasive appendiceal cohort, POCs were identified in 55% (n = 233) and OS and RFS did not differ between patients who experienced a complication and those who did not (OS 94 vs 94% p = 0.26; RFS 68 vs 60% p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased OS (59 vs 74% p < 0.001) and RFS (32 vs 42% p < 0.001). Infectious POCs were most common (35%; n = 196). On MV analysis accounting for gender, PCI and incomplete resection (CCR1), infectious POCs in particular were associated with decreased OS compared to no complication (HR 2.08 95%CI 1.48-2.93 p < 0.01) or other types of complications (HR 1.7 95%CI 1.28-2.25 p < 0.01). This association persisted for infectious POCs and reduced RFS (HR 1.61 95%CI 1.23-2.10 p < 0.01). Conclusions: Postoperative complications are associated with decreased OS and RFS after CRS/HIPEC for invasive histology, but not for an indolent disease like non-invasive appendiceal neoplasm. Of all complication types, infectious complications are the main driver for this association. The exact mechanism is not known, but may be immunologic. Efforts must target best practices and standardized prevention strategies to minimize infectious POCs.
Cytoreductive surgery in selected patients with metastatic gastric cancer treated with systemic chemotherapy.
Authors: Berger Yaniv , Schuitevoerder Darryl , Vining Charles Christian , Giurcanu Mihai , Posner Mitchell C. , Roggin Kevin K. , Polite Blase N. , Liao Chih-Yi , Eng Oliver , Catenacci Daniel V.T. , Turaga Kiran
Published: February 2020

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Background: Cytoreductive surgery (CRS – gastrectomy combined with metastasectomy) for non-palliative indications is controversial for patients with metastatic gastric adenocarcinoma (MGA). We hypothesized that CRS in addition to systemic chemotherapy is associated with an improved survival when compared to patients with MGA receiving chemotherapy alone. Methods: Patients with MGA who received systemic chemotherapy between 2004-2016 were identified using the National Cancer Database (NCDB). Nearest neighbor 1:1 propensity score matching of demographic, tumor-related and treatment-related factors was used to create comparable groups. Overall survival (OS) was compared between subgroups using Kaplan-Meier analyses. Immortal bias analysis was performed among those that survived at least 90 days. Results: We identified 29,728 chemotherapy-treated patients who were divided into 4 subgroups: No surgery (NS, n = 25,690), metastasectomy alone (n = 1170), gastrectomy alone (n = 2248) and CRS (n = 620) with a median OS of 8.6, 10.9, 14.8 and 16.3 months, respectively (p < 0.001). Compared to patients who underwent no surgery, patients who underwent CRS were younger (58.9±13.4 vs. 62.0±13.1 years), had lower proportion of disease involving multiple sites (5.0% vs. 26.2%), and were more likely to have clinically occult disease (cM0 58.9% vs. 7.3%) - all p < 0.001. OS for propensity matched patients who underwent CRS (n = 490) was longer than NS (16.3 vs. 8.8 months, p < 0.001), including those with clinical M1 stage (n = 203) in both unmatched and propensity matched (median OS 19.7 vs. 8.6 months, p < 0.001) cohorts. On Cox regression model using the matched data, the hazard ratio for CRS vs. NS was 0.80 (95%CI 0.76-0.84). In the immortal matched cohort, the corresponding median OS was 16.7 vs. 9.7 months, p < 0.001. Conclusions: CRS in addition to systemic chemotherapy may be associated with an OS benefit in a selected group of patients with metastatic gastric adenocarcinoma. Suboptimal matching for tumor burden is our major limitation. In contrast to studies that focus on gastrectomy alone in the setting of MGA, this study highlights the role of CRS among patients receiving systemic chemotherapy.
Molecular characterization of a gastric cancer transmitted from an organ donor to four transplant recipients.
Authors: Atreya Chloe Evelyn , Park Meyeon , Grenert James P. , Behr Spencer , Gonzalez Amalia , Chou Jonathan , Maisel Samantha , Friedlander Terence W. , Freise Chris E. , Shoji Jun , Semrad Thomas John , Chin-Hong Peter , Collisson Eric A. , Van Ziffle Jessica
Published: February 2020

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Background: Donor-derived malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. Early recognition of donor-derived malignancy has treatment implications. We describe the molecular characterization of a gastric cancer transmitted from an organ donor to heart, liver (LR), left kidney (LKR), and right kidney-pancreas (KPR) recipients. Methods: IRB approval for chart review was obtained; LR, LKR, and KPR also provided research consent for molecular profiling. Short Tandem Repeat (STR) genotyping was performed by polymerase chain reaction and gel electrophoresis. Tumor and germline DNA from patients and the organ donor were subjected to next generation sequencing (NGS) of 479 genes. Fluorescence in situ hybridization (FISH) was used to confirm MET amplification. Results: Donor origin was established by STR analysis, with the tumors showing high levels of donor alleles. Pathology revealed a poorly differentiated adenocarcinoma with signet ring features. Immunohistochemical staining and CA-19-9 elevation were most consistent with gastric or pancreas origin. Tumor sequencing was notable for somatic mutation of CDH1, MET amplification and wild-type KRAS genes. Tumors from LR and KPR were nearly identical based on pathogenic variants, allele frequency, and copy number variation. Insufficient tumor cellularity in all LKR specimens precluded NGS profiling, but clinical testing found that the cancer was mismatch repair proficient; ERBB2 equivocal; and PDL-1 positive. A circulating tumor DNA test did not uncover any genomic alterations; however, MET amplification was confirmed in this tumor using FISH probes. Conclusions: STR analysis and reporting should be standard immediately following diagnosis of cancer in an organ transplant recipient to ascertain donor derivation. Further molecular characterization, including NGS, may aid in defining primary tumor origin. Here, diagnosis with PDL1-positive gastric cancer enabled use of pembrolizumab. One patient remains alive and without evidence of cancer following prompt organ explant after cancer was reported in other recipients.
A retrospective multicenter study evaluating the efficacy and safety of irinotecan in patients with advanced gastric cancer: Analysis of albumin-bilirubin (ALBI) grade.
Authors: Motoo Iori , Komatsu Yoshito , Yuki Satoshi , Nakano Shintaro , Nakatsumi Hiroshi , Kawamoto Yasuyuki , Muranaka Tetsuhito , Sawada Kentaro , Ando Takayuki , Miyagishima Takuto , Harada Kazuaki , Kobayashi Yoshimitsu , Hatanaka Kazuteru , Ishiguro Atsushi , Tanimoto Aya , Honda Takuya , Dazai Masayoshi , Sasaki Takahide , Sakamoto Naoya
Published: February 2020

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Background: It is important to predict prognosis and risk of adverse events in patients with advanced gastric cancer receiving chemotherapy. Albumin-bilirubin (ALBI) grade is recently used as liver function assessment and prognosticator in hepatocellular carcinoma. Irinotecan is metabolized in the liver, so ALBI score may be useful for predicting irinotecan efficacy and safety. Methods: We conducted a retrospective multicenter study and investigated association between efficacy and ALBI grade in patients who received irinotecan monotherapy between January 2010 and December 2017. All patients had to receive fluoropyrimidine and platinum as prior therapy. The ALBI score is calculated by the equation: ALBI score = (log10 bilirubin [µmol/L] × 0.66) + (albumin [g/L] × −0.0852). As a result, ALBI grades 1, 2, and 3 were developed as follows: ALBI score ≤ −2.60 (ALBI grade 1), > −2.60 to ≤ −1.39 (ALBI grade 2), and > −1.39 (ALBI grade 3). Results: The number of patients with ALBI grade 1/2/3 is 100/68/5. In ALBI 1/2-3 patients, performance status 0/1/≥2 was 37/57/6 and 17/43/14, treatment line 2nd/3rd or later was 58/42 and 21/53, HER2 positive/negative 14/86 and 16/58, respectively. In ALBI 1/2-3 patients, median PFS was 3.3 and 2.3 months (HR = 0.684, P = 0.018) and median OS was 11.7 and 6.7 months (HR = 0.492, P < 0.001), respectively. In ALBI 1/2-3 patients, median treatment cycle which was 6 and 4 ( P = 0.09) and RDI were significantly different was, and RDI was 0.80 vs 0.70( P = 0.027), respectively.Hematological AEs were observed in 88% and 87% ( P = 1.000), severe hematological AEs (≥G3) were 41% and 58%( P = 0.040). Non-hematological AEs were 87% and 86%( P = 1.000), severe non-hematological AEs (≥G3) were 11% and 18% ( P = 0.257), respectively. Severe AEs in more than 5% patients were leukopenia (12% and 18%), neutropenia (23% and 28%), anemia (16% and 31%), and anorexia (2% and 10%).In multivariate analysis, ALBI grade was associated with shorter OS (ALBI 1 and 2-3: HR 1.773 95%C.I. 1.184-2.654, p = 0.005). Conclusions: ALBI grade might be both prognostic factor and risk factor in treatment with irinotecan monotherapy for patients with AGC.
Development of a gene panel for 18F-FDG PET positivity prediction in gastric cancer.
Authors: Bae Seong-Woo , Berlth Felix , Choi Hongyoon , Jeong Kyoung-Yun , Min Jimin , Park Ji-Hyeon , Choi Jong-Ho , Park Shin-Hoo , Kong Seong-Ho , Park Do Joong , Lee Hyuk-Joon , Chung June-Key , Yang Han-Kwang
Published: February 2020

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Background: 18F-FDG PET is widely used in clinical cancer diagnostics. However, 18F-FDG PET scan in gastric cancer (GC) is still controversial because of its lower sensitivity in diagnosis and staging compared to other imaging modalities. The purpose of this study was to establish a gene panel for 18F-FDG PET positivity in GC by using patient-derived xenografts (PDXs). Methods: BALB/c nude mice were subcutaneously implanted with 30 cases of GC PDX tissues and underwent a simultaneous PET/MRI scanner. Using RNA-seq data of the 30 GC PDXs for training set, we constructed a gene co-expression network which was correlated with the maximal standardized uptake values (SUVmax). The least absolute shrinkage and selection operator (LASSO) was used for identification of genomic signature for the PET positivity and a prediction model was established. By using qRT-PCR, a gene panel (PredictionScore) based on the gene signature was developed. Results: We found that the PDXs could recapitulate FDG avidity of those parental tumors between 15 Patient-PDX pairs (Spearman r = 0.54, p-value = 0.04). The prediction model with the identified five genes ( PLS1, PYY, HBQ1, SLC6A5, NAT16) provided excellent prediction values compared with actual SUVmax for 15 patients as a validation set (Spearman r = 0.56, p-value = 0.03) and for 8 patients as a test set (Spearman r = 0.90, p-value = 0.005). The PredictionScore showed significant positive correlation with the actual SUVmax for 7 patients as an external validation set (Spearman r = 0.82, p-value = 0.03). Conclusions: PDX can be used to develop a gene panel for the PET positivity prediction in GC. Our results showed that the scoring system can be clinically applicable for developing a predicted stratification model. Future studies will aim to evaluate the panel for a higher number of PET-scanned GC patients to establish a rational patient selection for PET scan in clinical settings.
Comparison of immune-related gene expression between primary and metastatic site in advanced gastric cancer patients with peritoneal dissemination.
Authors: Takahashi Naoki , Matano Yutaka , Tsujibata Akihiko , Murayama Kozue , Miyazawa Shoichi , MATSUSHIMA TOMOHIRO , Shimizu Satoshi , Kumekawa Yosuke , Yoshii Takako , Asayama Masako , Hara Hiroki
Published: February 2020

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Background: Immune checkpoints inhibitor (ICI) is effective and approved in some solid tumors including advanced gastric cancer (GC). Peritoneal dissemination is known as a poor prognostic factor and was reported to be associated with the resistance to ICI according to the previous reports. The aim of our study is to compare the immune-related gene expression between primary site and peritoneal lesion in advanced GC patients. Methods: Among advanced GC patients, we selected those who underwent surgical resection for both primary and peritoneal lesions simultaneously. Formalin-fixed paraffin-embedded (FFPE) tumor tissues of primary and peritoneal lesions were prepared and RNA was extracted by Maxwell RSC RNA FFPE kit (Promega). Immune-related gene expression was evaluated by using nCounter Max Analysis System (NanoString). We used nCounter PanCancer Immune Profiling Panel Kit which includes 770 immune-related genes. Results: Immune-related gene expression was evaluated by using twenty-four FFPE tumor tissues in twelve GC patients. Scatter plot and hierarchical clustering analyses showed that the pattern of immune-related gene expression was not much different between primary and peritoneal lesions beyond the individual differences. Regarding the T cell function, high expression of Immune-related genes was widely detected in patients with EB virus-positive (n = 2) and HER2-positive (n = 1). Gene expressions such as CD70, FAS, MAF and IL-3 were higher in peritoneal lesion compared with primary lesion (p < 0.05). Whereas, expressions of F2RL1 and IL-11 were lower in peritoneal lesion compared with primary lesion (p < 0.05). Conclusions: Our study indicated that there was not much difference of Immune-related gene expression between primary and peritoneal lesion in advanced GC patients. Positive status of EB virus and HER2 may be associated with high expression of immune-related genes. Further analysis to evaluate immune-related gene expression between primary and metastatic site may contribute the further understanding of cancer immunity in advanced GC.
Tumor microenvironment evaluation to predict pembrolizumab benefit of metastatic gastric cancer: Results from phase II clinical trial.
Authors: Zeng Dongqiang , Liao Wangjun , Shi Min , Zhou Rui , Huang Na , Yu Yunfang , Peng Wenying , Wu Jiani , Ye Zilan
Published: February 2020

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Background: Clinical studies support the efficacy of immune checkpoint blockades (ICBs) in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response to ICBs, we performed molecular characterization of tissues from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial (NCT#02589496). Methods: Of 61 patients, 60 patients underwent pretreatment biopsy and 45 specimens were of sufficiently high quality for RNA sequencing. TMEscore, which was previously established to quantify the tumor microenvironment (TME), was used to estimated TME of pretreatment specimens. The predictive value and correlation of integrative molecular characterization were systematically explored. Results: We established a methodology (TMEscore) to evaluated the TME of GC patients, which was previously found to be a robust prognostic and predictive biomarker for patients treated with ICBs. By applying ROC curve analysis, the TMEscore was found to be a best predictive biomarker (TMEscore: AUC = 0.891; CPS: AUC = 0.830; TMB: AUC = 0.672; MSI status: AUC = 0.708; EBV status: AUC = 0.727; respectively). Moreover, TMEscore was the most significant gene signature that correlated with tumor response (TMEscore: P = 1.7 × 10 −5; GEPs: P = 0.00035; ImmunoScore: P = 0.29106; CD8+ T cell fraction: P = 0.00011; Immune checkpoint score: P = 0.00149; respectively). TMB was not correlated with TMEscore (Kruskal-Wallis test, P = 0.14). A higher TMEscore was significantly associated with EBV+ and high-MSI TCGA molecular subtypes (Kruskal-Wallis test, P = 0.002) which were reported to benefit from ICBs of GC. Conclusions: These findings indicate that the assessment of TMEscore via high throughput-sequencing and PCA algorithm provides a robust biomarker for the selection of GC patients who may derive greater benefit from pembrolizumab. Our data also suggest that TMEscore may be a more accurate predictive biomarker than TMB, MSI and EBV status, and this resource may help facilitate the development of precision immunotherapy. Clinical trial information: NCT#02589496.