bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple primary cancers in patients with gastric cancer: A retrospective study in China National Cancer Center.
Authors: Lei Qi , Zhang Runfeng , Zou Xi , Zhou Aiping , Du Chun-Xia
Published: February 2020

337

Background: Gastric cancer (GC) is common in China. With the total incidence of cancer keeping rising in China, the occurrence of multiple primary cancers with GC is growing. Early detection and diagnosis of second or more primary cancers are vital for patients’ survival. Methods: Patients with multiple primary cancers containing gastric adenocarcinoma treated in China National Cancer Center from January 2010 to December 2017 were included. A 6-month interval was used to separate synchronous and metachronous cancers (according to IARC/IACR criteria). Results: 479 patients met the criteria were included, with 452 (94.4%), 24 (5.0%), 3 (0.6%) patients having two, three or more primary cancer sites respectively, contributing a total of 510 cancer sites besides stomach (Table). Malignancies at 257 (50.4%) sites occurred with GC synchronously, while 253 (49.6%) occurred metachronously. The median age at the diagnosis of first cancer was 59 (interquartile range [IQR], 53-66) years. The median interval between the diagnosis of first primary cancer and metachronous second one was 50.3 (IQR, 23.7-97.0) months. Cancers outside gastrointestinal (GI) tract were more likely to occur with GC metachronously, while GI tract cancers were more likely to occur synchronously (χ²=55.36, p<0.001). Out of 479 patients, there were 352 (73.6%) male and 127 (26.4%) female. The most common associated cancer was esophagus cancer (142, 40.3%) in male, and breast cancer (31, 25.4%) in female. 236 (49.8%) patients were current smokers or ex-smokers, and 190 (40.1%) were regular alcohol consumers. 110 (23.2%) had first-degree relative cancer family history, with 84 (17.7%) having GI tract cancer family history. Conclusions: GI tract including esophagus and colorectum should be carefully scrutinized during GC peri-operation period. Further genetic research is warranted to explore the potential pathogenesis of multiple primary cancers.[Table: see text]
Economic impacts of care by high-volume providers for noncurative esophagogastric cancer: A population-based analysis.
Authors: Hallet Julie , Look Hong Nicole , Zuk Victoria , Davis Laura , Gupta Vaibhav , Earle Craig , Mittmann Nicole , Coburn Natalie
Published: February 2020

339

Background: Esophagogastric cancer (EGC) is one of the deadliest and costliest malignancies to treat. Care by high-volume providers can provide better outcomes for patients with EGC. Cost implications of volume-based cancer care are unclear. We examined the cost-effectiveness of care by high-volume medical oncology providers for non-curative management of EGC. Methods: We conducted a population-based cohort study of non-curative EGC over 2005-2017 by linking administrative healthcare datasets. High-volume was defined as >11 patients/provider/year. Healthcare costs ($USD/patient/month-survived) were computed from diagnosis to death or end of follow-up from the perspective of the healthcare system using validated costing algorithms. Multivariable quantile regression examined the association between care by high-volume providers and costs. Sensitivity analyses were conducted by varying costing horizons and high-volume definitions. Results: Among 7,011 non-curative EGC patients, median overall survival was superior with care by high-volume providers with 7.0 (IQR: 3.3-13.3) compared to 5.9 (IQR: 2.6-12.1) months (p < 0.001) for low-volume providers. Median costs/patient/month-lived were lower for high-volume providers ($5,518 vs. $5,911; p < 0.001), owing to lower inpatient acute care costs, despite higher medication-associated and radiotherapy costs. Care by high-volume providers was independently associated with a reduction of $599 per patient/month-lived (95% confidence interval: -966 to -331) compared to low-volume providers. The incremental cost-effectiveness ratio was -393. Care by high-volume providers remained the dominant strategy when varying the high-volume definition and the costing time horizon. Conclusions: Care by high-volume providers for non-curative EGC is associated with superior survival and lower healthcare costs, indicating a dominant strategy that may provide an opportunity to improve cost-effectiveness of care delivery.
A phase II trial of low-dose nab-paclitaxel for patients with previously treated or recurrent advanced gastric cancer (OGSG1302).
Authors: Hirota Masashi , Tamura Shigeyuki , Taniguchi Hirokazu , Takeno Atsushi , Imamura Hiroshi , Fujita Junya , Matsuyama Jin , Kimura Yutaka , Kawada Junji , Hirao Motohiro , Nishikawa Kazuhiro , Fujitani Kazumasa , Kurokawa Yukinori , Sakai Daisuke , Kawakami Hisato , Shimokawa Toshio , Satoh Taroh
Published: February 2020

350

Background: Paclitaxel is a key drug in second-line chemotherapy for advanced or recurrent gastric cancer (AGC) and nanoparticle albumin-bound paclitaxel (nab-PTX) is also widely used in Japan. A previous phase II trial in Japan showed the effectiveness of nab-PTX (260 mg/m2) administered every 3 weeks (q3w) in patients with AGC with a response rate (RR) of 27.8%; however, toxicity was major concern with grade ≥3 neutropenia (49.1%) and peripheral neuropathy (23.6%). To solve this problem, we investigated the efficacy and safety of low-dose q3w nab-PTX regimen in AGC. Methods: Eligibility requirements included: aged ≥20 years, HER2-negative, histologically confirmed, unresectable or recurrent gastric adenocarcinoma, one or more prior chemotherapy containing fluoropyrimidine regimens, presence of measurable lesion(s) according to RECIST ver. 1.1, ECOG PS of 0–2, and adequate organ function. Nab-PTX was administered at a dose of 220 mg/m2 every 3 weeks. The primary endpoint was the RR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity and proportion of patients who received subsequent chemotherapy. Results: Thirty-three patients were enrolled from 10 institutions in Japan. Of the 32 patients treated with protocol therapy, RR (CR, PR) was 3.1% (95% CI, 0–16.2%), which was not reached the protocol-specified threshold (p = 0.966). DCR (CR, PR, SD) was 37.5% (95% CI, 21.1–56.3%), median OS and PFS were 6.3 months (95% CI, 4.4–14.2) and 2.2 months (95% CI, 1.8-3.1). Relative dose intensity was 97.8% (215 mg/m2). 62.5% of patients received subsequent chemotherapy. Most common grade ≥3 adverse events were neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). Conclusions: Low-dose regimen of q3w nab-PTX was slightly less toxic, although it did not demonstrate the same effect as the original regimen in response rate. Therefore, it is not recommended for AGC in second or later line setting. Clinical trial information: UMIN 000012701.
Survival benefit of conversion therapy after intensive chemotherapy for unresectable metastatic gastric cancer: A propensity score-matched analysis.
Authors: Ohnuma Hiroyuki , Sato Yasushi , Omori Ginji , Onoyama Naoki , Ameda Saki , Ito Ryo , Hamaguchi Kota , Hayasaka Naotaka , Sato Masanori , Murase Kazuyuki , Takada Kohichi , Miyanishi Koji , Ito Tatsuya , Nobuoka Takayuki , Takemasa Ichiro , Kato Junji
Published: February 2020

354

Background: The significance of conversion therapy (CT), whereby patients (pts) with unresectable disease respond to chemotherapy and subsequently receive surgery with curative intent (adjuvant surgery: AS), has been specifically established for metastatic colorectal cancer. However, such a strategy for advanced or recurrent gastric cancer (AGC) remains controversial. This study aims to clarify the clinical significance of CT for AGC. Methods: In this retrospective multi-institution observational study, we analyzed 168 AGC pts who received chemotherapy consisting of docetaxel, cisplatin or oxaliplatin, and S-1 ± trastuzumab between 2003 and 2019. We divided pts into two groups: those who underwent CT (group CT) or chemotherapy only (group C). Propensity score analysis with 1:1 matching minimized confounding bias when comparing efficacy and safety between groups. Results: A tumor response to chemotherapy was observed in 82.4% of all cases, while 34.5% (58/168) underwent AS. Fifty-one of the 58 pts underwent an R0 resection, and 79.3% were deemed histological responders. After matching, 44 pairs of C and CT pts were selected; significant differences in baseline characteristics were not observed. Incidences of adverse events during chemotherapy were similar between groups, with neutropenia and febrile neutropenia as common grade 3–4 events. Compared with group C, group CT had a significantly better median overall survival (OS) (15.5 vs. 46.0 months; hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.18–0.58; p < .001), and a prolonged progression-free survival (6.5 vs.22.6 months; HR 0.33; 95% CI 0.19–0.56; p < .001). Subgroup analysis of OS showed a favorable trend for CT for almost all parameters. In a multivariate analysis, ECOG performance status (HR 0.10; 95% CI 0.03–0.31) and AS (HR 0.20; 95% CI 0.10–0.40) correlated with favorable OS. In the CT group, pathological response was an independent prognostic factor (HR 0.16; 95% CI 0.06–0.39). Conclusions: CT was associated with better outcomes in AGC pts, even after baseline adjustment. Our data warrants further large-scale studies to establish a conversion therapeutic strategy.
Chemotherapy-induced neutropenia with FOLFOX in the adjuvant treatment of colorectal cancer.
Authors: Gotfrit Joanna , Marginean Horia , Maroun Jean Alfred , Trincao-Batra Sara , Asmis Timothy R. , Vickers Michael M. , Goodwin Rachel Anne
Published: February 2020

38

Background: Patients undergoing adjuvant treatment with FOLFOX for colorectal cancer (CRC) are at risk of developing chemotherapy-induced neutropenia (CIN). We assessed the risk of CIN and the use of granulocyte colony stimulating factor (GCSF). Methods: We performed a retrospective chart review of patients with CRC treated with FOLFOX at our institution from 2013 - 2015. Demographic and treatment data were collected. CIN was defined as ANC <1.5, and all episodes of neutropenia were assumed to be the result of chemotherapy. Results: A total of 302 patients were included (baseline demographics in Table). In the overall cohort, 174 (58%) of patients had at least 1 episode of CIN. The risk CIN was 47% in stage II, 60% in low risk stage III (T1-3 and N1), and 58% in high risk stage III (T4 or N2). Among patients with at least 1 episode of CIN, the 1st CIN event occurred during the 1st 3 months of treatment in 76%, and the median cycle of 1st occurrence was 4 (95% CI 4-5), which did not differ by stage. Among patients who had at least 1 episode of CIN, 112 (64%) had a 2nd episode at a median cycle of 9 (95% CI 8-10). Among patients with at least 1 episode of CIN, 79 (45%) received subsequent GCSF, initiated 1 cycle after the 1st CIN event 37% of the time. Among patients with at least 2 episodes of CIN (n=112), 58 (52%) received GCSF after the 1st or 2nd event. Of these, 40 patients (69%) started GCSF newly after the 2nd CIN event. Among patients starting GCSF after the 2nd CIN event, 47% initiated GCSF 1 cycle later. The median cycle at which the relative dose intensity of FOLFOX decreased to <85% was cycle 6 (95% CI 5-8) in those with no CIN events, cycle 3 (95% CI 2-4) in those with at least 1 CIN event treated with GCSF, and cycle 5 (95% CI 4-6) in those with at least 1 CIN event treated without GCSF. Conclusions: CIN is a frequent occurrence during the adjuvant treatment of CRC with FOLFOX and most often occurs in the first 3 months of treatment. While oncologists may treat some patients with 3 months of FOLFOX rather than 6, physicians must be aware of CIN regardless of the planned duration of treatment. Early initiation of GCSF may be a consideration.

[Table: see text]
S-1+oxaliplatin with pembrolizumab for advanced gastric cancer: The cohort 1 in a phase IIb KEYNOTE-659 study.
Authors: Yasui Hisateru , Kawazoe Akihito , Yamaguchi Kensei , Negoro Yuji , Azuma Mizutomo , Amagai Kenji , Hara Hiroki , Baba Hideo , Tsuda Masahiro , Hosaka Hisashi , Kawakami Hisato , Oshima Takashi , Omuro Yasushi , Machida Nozomu , Esaki Taito , Yoshida Kazuhiro , Nishina Tomohiro , Komatsu Yoshito , Han Shi Rong , Shitara Kohei
Published: February 2020

382

Background: The KEYNOTE-059 study showed the preliminary antitumor activity and tolerability of chemotherapy with pembrolizumab (P) for advanced gastric cancer (AGC). In Japan, S-1 + platinum regimen is a standard chemotherapy for AGC. The KEYNOTE-659 study (NCT03382600) investigated the efficacy and safety of S-1 + oxaliplatin (SOX; cohort 1) or cisplatin (SP; cohort 2) with P as the first line treatment in patients (pts) with human epidermal growth factor receptor 2 (HER2)-negative, programmed death-ligand 1 (PD-L1)-positive AGC. Here, we report the results of cohort 1. Methods: The key inclusion criteria were as follows: age ≥18 to ≤75 years; an ECOG performance status of 0 or 1; and chemotherapy-naïve, HER2-negative and PD-L1-positive AGC. PD-L1 positivity was defined as a combined positive score of ≥1 using the IHC 22C3 PharmDx assay. An S-1 dose of 40-60 mg per dose was orally administered, twice daily, for the first 2 weeks of a 3-week cycle. P (200 mg) and oxaliplatin (OX; 130 mg/m2) were administered on day 1 of each cycle. The primary endpoint was overall response rate (ORR) that was assessed by a blinded independent central review (BICR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. Results: From April to September 2018, 54 pts were enrolled at 25 sites in Japan. The median follow-up time was 10.1 months. The median number of P doses and cycles in SOX were 9 (range, 2-18) and 6 (range, 2-13), respectively. The relative dose intensities of S-1 and OX were 73% and 60%, respectively. The ORR and DCR assessed by BICR were 72.2% (95% CI 58.4-83.5) and 96.3% (95% CI 87.3-99.5), respectively. The median PFS was 9.4 months (95% CI 6.6-NR). Median DOR and OS were not reached. Grade ≥3 adverse events (AEs) were reported in 31 pts (57.4%). The most common treatment-related AEs of grade ≥3 were thrombocytopenia (14.8%), neutropenia (13.0%), colitis (7.4%), and adrenal insufficiency (5.6%). There were no treatment-related deaths. Conclusions: This study showed the encouraging efficacy and manageable safety of SOX with P therapy as a first line in pts with HER2-negative, PD-L1-positive AGC. Clinical trial information: NCT03382600.
Comparison of efficacy of aspirin plus epirubicin, oxaliplatin, and capecitabine versus epirubicin, oxaliplatin, and capecitabine alone in patients with locally advanced and metastatic gastric cancer: A randomized clinical trial.
Authors: Jafa Esha , Dubashi Biswajit , Kayal Smita , Kate Vikram , Ganesh Rajesh Nachiappa , C. Sunitha V. , L. Charles , Nisha Yadav
Published: February 2020

384

Background: Aspirin was long known to prevent cancer, the last decade revealed its therapeutic role via varied mechanisms like inhibition of platelet activation, COX and PI3K pathway. Since PI3K/AKT/mTOR is one of the pathways activated in gastric cancer and Giampieri et al (2016) showed improved response rates, PFS and OS with addition of aspirin to capecitabine in heavily pretreated metastatic colorectal cancer,a cancer in which efficacy of aspirin is related to presence of PI3K mutations,we aimed to compare the efficacy of aspirin added to a standard regime EOX with EOX alone in locally advanced and metastatic gastric cancer. Methods: All patients with advanced gastric cancer coming to JIPMER,Department of Medical oncology between march 2017 to may 2019 were screened for eligibility in the trial.Those eligible were randomly assigned to standard EOX or standard EOX plus 150 mg of daily aspirin.Tumor measurements were performed at baseline,then after 3-4 cycles (interim response) and the response to treatment was assessed by the radiologist who was blinded to treatment arms according to RECIST1.1 criteria.Toxicity profiles were recorded as per CTCAE v 4.03.In per protocol analysis,response rates, PFS(progression free survival) and OS (overall analysis) were analysed for patients who received ≥3 cycles and had an evaluable interim response. Results: 95 patients were randomised.In per protocol analysis, 70 patients were included. The results are shown in table. Conclusions: No statistically significant difference was seen with respect to response rates, PFS, OS and toxicity, although there was a higher ORR (overall response rate=complete response,CR +partial response, PR) and OS seen in EOX plus aspirin arm. Clinical trial information: CTRI/2017/11/010651. JIPMER,Puducherry,India [Table: see text]
Treatment efficacy of ramucirumab-based chemotherapy in patients with alpha-fetoprotein producing gastric cancer (AFPGC).
Authors: Kamiimabeppu Daisaku , Wakatsuki Takeru , Takahari Daisuke , Fukuda Naoki , Osumi Hiroki , Nakayama Izuma , Ogura Mariko , Sato Tarou , Ooki Akira , Shinozaki Eiji , Suenaga Mitsukuni , Chin Keisho , Yamaguchi Kensei
Published: February 2020

389

Background: AFPGC is an aggressive subgroup of gastric cancer and is associated with a worsened survival because of a high incidence of liver metastasis. Ramucirumab-based chemotherapy is the standard treatment as a second line in advanced gastric cancer. Recently ramucirumab has showed survival benefit in hepatocellular carcinoma, but only those with higher AFP levels. However, the efficacy of ramucirumab in AFPGC is unknown. Methods: We retrospectively assessed 283 patients who received paclitaxel or nab-paclitaxel combined with ramucirumab between July 2015 and December 2018. AFPGC was defined when serum AFP levels were elevated and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal when diagnosed. Other patients were excluded. Patients’ demographics, progression-free survival (PFS), overall survival (OS) and objective response rates (ORR) were compared between the two groups. Results: Among the 283 patients, 24 patients were AFPGC and 189 patients were non-AFPGC. AFPGC was associated with high incidences of intestinal histology (46%) and liver metastasis (63%), while AFPGC was associated with a low incidence of peritoneal metastasis (21%), compared with non-AFPGC. There was no significant difference in PFS and OS between the two groups. Median PFS were 5.4 (95%CI 3.6-6.7) months in AFPGC and 4.1 (3.7-5.1) months in non-AFPGC (HR 0.93 95%CI 0.60-1.46, p = 0.788), respectively. Median OS were 19.0 (95%CI 13.2-NA) months in AFPGC and 19.3 (17.9-20.1) months in non-AFPGC (HR 1.21 95%CI 0.70-2.10, p = 0.494), respectively. Regarding with ORR, AFPGC showed higher ORR with 52.6% (95%CI 30.2-75.1), while 37.3% (95%CI 26.4-48.3) in non-AFPGC (p = 0.296), although this was not statistically significant. Conclusions: Ramucirumab showed comparable survival and higher ORR in AFPGC than in non-AFPGC. Considering the generally poor prognosis of AFPGC, it is speculated that ramucirumab may have compensated for disadvantage in survival.
Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma.
Authors: Ly Michele , Molena Daniela , Sihag Smita , Wu Abraham Jing-Ching , Shah Pari M. , Gu Ping , Sugarman Ryan , Maron Steven Brad , Chalasani Sree Bhavani , Shcherba Marina , Yeh Randy , Tang Laura H. , Alterman Carly , Collins Paige , Cowie Kendall , Janjigian Yelena Yuriy , Ilson David H. , Ku Geoffrey Yuyat
Published: February 2020

394

Background: We previously presented safety data for the combination of D with carboplatin/paclitaxel (C/P) and RT for locally advanced esophageal cancer (J Clin Oncol 2018;36:172 [abstr]). Based on the positive results of the CALGB 80803 study (J Clin Oncol 2017;35:1 [abstr]), we amended the study to administer induction FOLFOX prior to PET assessment. Here, we present updated results. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I-III GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received mFOLFOX6 ×2 prior to repeat PET/CT. PET responders (PETr) received 5-FU or capecitabine and oxaliplatin with RT to 50.4Gy, while PET non-responders (PETnr) received C/P with RT. All Pts received D 1,500 mg q4W ×2 starting 2 wks prior to and during CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg q4W ×6. Results: 20 Pts have been enrolled: 16 GEJ, 4 esophageal; 3 T1-2N+, 8 T3-4N0, 1 T3Nx, 8 T3-4N+. 13 of 20 Pts (65%) are PETr. Of 13 Pts who have had surgery (8 PETr, all R0), pathologic complete response (pCR) was seen in 3 (23%; 2 PETr); 3 Pts (23%; all PETr) had ypT1bN0 tumors with 99% response and 1 Pt (8%; PETnr) had ypT0N1 (1/30 LN) with profound response in LN. 2 Pts had MSI tumors (1 PETr; 1 pCR, 1 ypT2N0 with 90% response). Notable gd 3/4 adverse events (AEs) observed were lymphopenia in 16 Pts (80%), neutropenia in 4 Pts (20%) and diarrhea and dysphagia in 1 Pt each (5%). Notable gd 1/2 AEs in ≥20%: thrombocytopenia (18 Pts), fatigue (13 Pts), anemia (12 Pts), increased AST (12 Pts), constipation (11 Pts), nausea (11 Pts), diarrhea (7 Pts) and odynophagia (7 Pts). Immune-related AEs noted were gd 3 hepatitis and gd 2 dermatitis in 1 Pt and gd 1 hypothyroidism in 1 Pt. Median length of post-op stay is 8 days, with 18% anastomotic complication rate. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT is safe and feasible. pCR and near-pCR in ½ of Pts is encouraging and compares favorably to our historical pCR rate of 15% in PETr (Cancer 2016:122:2083) and pCR rate of 31% in CALGB 80803 Pts who received induction FOLFOX. Accrual to 36 Pts continues and updated outcomes and immune correlative data will be presented. Clinical trial information: NCT02962063.
Neoadjuvant chemotherapy with docetaxel plus oxaliplatin and S-1 for locally advanced, resectable gastric or gastro-esophageal junction adenocarcinoma: Short-term results from a phase II trial.
Authors: Kawase Tomono , Kurokawa Yukinori , Kobayashi Noboru , Takeno Atsushi , Kawabata Ryohei , Takahashi Tsuyoshi , Yamasaki Makoto , Doki Yuichiro
Published: February 2020

397

Background: In locally advanced, resectable gastric or gastro-oesophageal junction (EGJ) adenocarcinoma, perioperative the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) is the standard chemotherapy in Europe. However, there is no evidence of neoadjuvant chemotherapy for resectable gastric cancer in Japan. Therefore, we conducted a phase II trial of neoadjuvant chemotherapy with docetaxel plus oxaliplatin, and S-1 (DOS) for locally advanced, resectable gastric or EGJ adenocarcinoma. Methods: Eligible patients had histologically confirmed gastric or EGJ adenocarcinoma of a clinical Stage III according to the 14th Edition of Japanese Classification of Gastric Carcinoma. DOS was administered for two or three preoperative cycles followed by eight postoperative cycles of S-1. Each 3-week cycle of DOS consisted of docetaxel 40 mg/m2 and oxaliplatin 100 mg/m2 on day 1 plus S-1 80-120 mg/body on days 1 to 14. Primary endpoint was 3-year progression-free survival rate, and secondary endpoints included overall survival, progression-free survival, response rate, histological response rate, R0 resection rate, and adverse events. Results: Of 50 enrolled patients, 48 (37 gastric and 11 EGJ) were eligible for the analysis. 42 (88%) patients completed two or three preoperative cycles of DOS. The most common grade 3-4 adverse events of DOS were neutropenia (69%), leukopenia (56%), diarrhea (19%), and febrile neutropenia (13%). Of 45 patients who underwent gastrectomy, postoperative morbidities (Clavien-Dindo ≥Grade II) occurred in 12 (27%) patients. R0 resection could be achieved in 43 (90%) patients. 12 (27%) and 30 (67%) of 45 patients achieved pathological response rate of Grade2-3 and Grade1b-3, respectively. There was no treatment-related death. Conclusions: Neoadjuvant DOS for locally advanced, resectable gastric or EGJ adenocarcinoma might be favorable. Long-term results will be published in two years. Clinical trial information: 000017652.
Enhanced microbial diversity and chemoradiation response in HPV+ anal cancer.
Authors: Kouzy Ramez , Lin Daniel , Noticewala Sonal Suresh , Colbert Lauren Elizabeth , Taniguchi Cullen M.
Published: February 2020

4

Background: Anal cancer is a rare, but treatable, malignancy caused by the human papilloma virus (HPV). Because anal cancer is uncommon and carries a significant social stigma, this disease has rarely been studied in a prospective fashion, creating a large knowledge gap of which biological factors can improve treatment responses, particularly the microbiome which regulates many facets of oncobiology. Methods: We collected microbiome samples before, during, and after definitive chemoradiation for localized anal cancer as part of an IRB-approved institutional clinical trial (2017-0606). Samples were collected by a non-invasive swab biopsy that enabled collection of tumor cells and microbiome during standard-of-care treatment visits. Bacterial genomic DNA is extracted using MO BIO PowerSoil DNA Isolation Kit (MO BIO Laboratories) and the 16S rDNA V4 region is amplified by PCR and sequenced on the MiSeq platform (Illumina) using the 2x250 bp paired-end protocol, yielding pair-end reads that overlapped almost completely. Sequence read pairs are demultiplexed using unique molecular barcodes, and reads are merged using USEARCH version 7.0.1090 and grouped by organizational taxonomy units (OTU’s) representative of unique bacterial species. Responders are were those patients who had more than 60% tumor shrinkage by MRI at the midpoint of treatment, and all others were considered non-responders. Results: As of June 2019 we enrolled 17 patients and analyzed 14. The majority of patients (10/14, 71.4%) were responders but unfortunately, 4 patients developed in-field recurrences of their anal cancer within a year after their treatment ended and were all T3 or T4 tumors. We found that alpha-diversity of the microbiome did not change during chemoradiation, but non-responders exhibited a lower alpha diversity compared to responders at baseline. Furthermore, specific taxa were correlated with treatment response, which imply a basis for future therapy. Conclusions: The alpha diversity of the microbiome is correlated with treatment response in HPV+ anal cancer. The idenitification of specific bacterial species between responders and non-responder might pave the way for more effective therapeis in the future.
Regulation of gastric carcinoma development in gastric adenoma/dysplasia by crebzf inhibition via miRNA-421.
Authors: Kim Yu Jin , Kim Won Shik , Kim Sang Woo , Jung Woon Yong
Published: February 2020

410

Background: In our previous study, we identified three miRNAs (hsa-miR-421, hsa-miR-29b-1-5p, and hsa-miR-27b-5p) with two mRNAs (FBXO11 and CREBZF) that might play an important role in the development of gastric adenocarcinoma (GAC) from premalignant adenomas. However, the expression and function of these miRNAs have not been not well characterized. Methods: We investigated the roles of CREBZF and miRNAs as potential biomarkers for the progression of gastric cancer (GC) in low-/high-grade dysplasia and early gastric cancer patients using immunohistochemical staining and miRNA in situ hybridization. Considering that targets can modulate in GC, we analyzed the CREBZF expression in gastric cancer cell lines by RT-PCR and western blot analysis. Results: We observed lower expression of CREBZF with increasing miRNAs in the MKN-74 gastric cancer cells compared to that in SNU-NCC-19. Next, the role of CREBZF in MKN-74 gastric cancer cells was investigated via cell viability and migration assays by miRNA/anti-miRNA modulation. Furthermore, we found that hsa-miR-421/hsa-miR-29b-1-5p target CREBZF and might play an important role in the migration of MKN-74 cells. Conclusions: This study suggests that increased CREBZF by hsa-miR-421/hsa-miR-29b-1-5p inhibition may be important to prevent the progression of gastric cancer in its early stage.
Transcriptional profile of immune microenvironment and their prediction role for the prognosis of esophageal squamous cell carcinoma.
Authors: Guo Jianji , Liu Tao , Shi Xinying , Mao Beibei , Zhang Jiao , Zhang Henghui , Xian Lei
Published: February 2020

416

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancer in China. The genetic characterizations have already been described in many studies, but the immune microenvironment features were seldom reported. Our study was aimed to explore the relationship between the immune profile in stage IIIa ESCC and patients’ prognosis. Methods: 20 eligible stage IIIa ESCC patients with received surgery and radiotherapy (19 with and 1 without radiotherapy). RNA targeted sequencing was performed on 20 primary tumor specimens. Transcripts of 395 immune-related genes expressed in tumor were analyzed. The univariate and multivariate Cox proportional hazards analyses were examined the relations of 395 genes’ expression and the prognosis. Results: Patients were divided into two groups based on the median expression values of 395 genes. The univariate analyses showed 20 genes were significantly associated with overall survival (OS). Unsupervised hierarchical clustering analysis using 20 gene expression data revealed two distinct clusters (cluster 1 and 2). The cluster1 patients had high level expression of AXL, ADGRE5, CD40, CXCR6, MPO, etc., which were associated with tumor proliferation and migration. However, the cluster2 patients expressed higher NOS2, IL15, IKZF2, TNFRSF18 which were related with T lymphocyte activated. Therefore, the cluster2 patients had significantly longer OS than cluster 1. Moreover, the combined expression of 10 genes (CD40, ADGRE5, CSF1R, CCR1, IGSF6, MPO, MRC1, SRGN, CD63, LRP1) which had high correlation among 20 genes were significantly related to OS and DFS (disease free survival) in univariate analysis. The multivariate analyses demonstrated that 10 genes signature expression was the independent high risk factor for OS, and the low signature value was associated with better prognosis. Conclusions: In IIIa ESCC, the 20 genes can profile the tumor immune microenvironment, and were independently associated with the patients’ OS. The 10 genes’ signature which represents the malignancy and immune activation of tumor was an independent predictive factor for OS, which can identify the patients with favorable or poor prognosis.
Neutrophil-to-lymphocyte ratio as a prognostic factor and its relationship to patient (pt) outcomes in the RAINBOW trial.
Authors: Muro Kei , Ajani Jaffer A. , Wainberg Zev A. , Knoderer Holly , Wei Ran , Chatterjee Anindya , Abada Paolo , Ohtsu Atsushi
Published: February 2020

438

Background: Neutrophil-to-lymphocyte ratio (NLR/N) reflects underlying levels of systemic inflammation and has prognostic value in advanced gastric cancer (G/GEJ). We investigated the relationship between pretreatment NLR and clinical outcomes in the RAINBOW study of ramucirumab (R) with paclitaxel (P) in G/GEJ. Methods: NLR is defined as the ratio of absolute neutrophil count and absolute lymphocyte count from peripheral blood. Pts in ITT population with baseline NLR were analyzed. As no clear NLR cutoff is established in G/GEJ, multiple cutoffs (4, 5, 6) were evaluated and relationships between baseline NLR and efficacy endpoints examined. Median OS, PFS were estimated using Kaplan Meier method; prognostic effects on OS/PFS of baseline NLR subgroups (sg) and treatment effects on OS/PFS within each baseline NLR sg were evaluated using univariate Cox PH models. Results: Baseline characteristics were generally balanced between high NLR sg. Higher baseline NLR groups were associated with worse outcomes regardless of cutoff [mOS N < 4 vs ≥4: 9.2 (8.1, 10.3) vs 5.6 (4.8, 6.6), HR = 0.61 (0.49, 0.75); N < 5 vs ≥5: 8.6 (7.8, 9.6) vs 5.3 (4.5, 6.5), HR = 0.59 (0.47, 0.75); N < 6 vs ≥6: 8.6 (7.8, 9.6) vs 4.7 (4.2, 5.9), HR = 0.55 (0.43, 0.70)]. Consistent treatment benefits (R+P vs Placebo (PB)+P) were observed within high baseline NLR sg (Table). No new safety signals were observed. Conclusions: In this exploratory analysis of RAINBOW, pretreatment NLR ( < 4, 5, 6) were independent prognostic factors of improved survival. Treatment benefits with R+P was preserved within high baseline NLR levels defined by different cutoffs and was consistent with ITT results. Clinical trial information: NCT01170663.

[Table: see text]
Epstein-Barr virus associated gastric carcinoma at the United States-Mexico border: A single institution study.
Authors: Gaur Sumit , Subramani Ramadevi , Mcalice Meghan , Padilla Osvaldo , Castillo Brenda Sofia , Alshaban Ahmed , Laxmanswamy Rajkumar
Published: February 2020

440

Background: Globally, gastric cancer (GC) is the fourth most prevalent cancer, and the second leading cause of cancer related deaths. Epstein-Barr virus is implicated in the pathogenesis of 5-10% of gastric cancers. Based upon the results obtained from of the cancer genome atlas, EBV related GC is characterized by promoter hypermethylation, PIK3CA mutations (80%) and increased expression of PD-1 and PD-L1, making it an attractive target for molecularly targeted therapy and immunotherapeutic options. As such, a case can be made for routine testing for EBV in all GC patients. University medical center, El Paso is a tax payer funded safety net health system in El Paso country, TX. We conducted a pilot study to characterize the prevalence of EBV associated gastric cancer seen at this facility. Methods: After obtaining institutional review board (IRB) approval, we identified cases of GC that were diagnosed between January 1, 2008- and December 31-2017. A total of 104 cases were identified of which 17 samples were randomly selected. Pathology specimens were reviewed to identify grade, subtype (intestinal vs diffuse), degree of lymphocytic infiltration and presence/absence of H. pylori. Representative sections from archived tumors were used to perform in-situ hybridization to look for the presence of Epstein-Barr virus. Samples were analyzed using the Rembrandt In situ Hybridization and Detection Universal RISH& HRP Detection Kit for Epstein-Barr early RNA. Results: The median age of the 17 patients is 63 years with 59% being males. 95% self identified as Hispanic. 41% were smokers, 18% used alcohol. The mean BMI was 27.3. Forty one percent of gastric cancer cases were found in the body, 29% in the antrum, 12% in the cardia, and 6% in the fundus. Forty one percent of cases were Stage IV, 24% stage II, 17% Stage III and 17% Stage I. 95% of cases were high grade, 53% of them had signet ring features. 18% of samples were H. pylori positive. None of the seventeen samples tested positive for EBV. Conclusions: EBV does not seem to contribute significantly to the pathogenesis of gastric cancer in our local population. As such routine testing for EBV in all gastric cancer patients may not be a cost effective utilization of resources at our hospital.
Predictive role of mismatch repair deficiency (MMR-D) in patients receiving first-line fluoropyrimidine and platinum (F-P) doublet chemotherapy for metastatic and locally advanced unresectable gastric cancers (GC).
Authors: Chae Heejung , Ryu Min-hee , Park Young Soo , Park Yangsoon , Moon MeeSun , Kang Yoon-Koo
Published: February 2020

444

Background: Although adjuvant chemotherapy has been known to have a detrimental effect on MMR-D patients (pts) with resectable GC, it is unclear whether palliative chemotherapy for advanced GC would also adversely affect the survival outcome of MMR-D pts. Immune-checkpoint inhibitor (ICI) monotherapy was approved as a standard treatment for ≥ 3rd line of advanced GC and also showed a remarkable efficacy in MMR-D pts regardless of line of therapy. ICI is now being investigated in combination with 1st-line cytotoxic chemotherapy. Hence, we aim to evaluate the prognostic impact of MMR on cytotoxic chemotherapy in advanced GC. Methods: We reviewed our prospective database to identify pts with initally metastatic, recurrent and locally advanced unresectable GC who received F-P doublet from 2015 to 2018. MMR was assessed by immunohistochemistry with previously-collected tumor tissue and correlated with clinical characteristics and survival outcomes. Results: Out of 892 pts identified from the database, 543 underwent MMR test [382 initally metastatic (70.3%); 127 recurrent (23.3%); 32 locally advanced unresectable (6.3%)]. Median age was 58 years (range, 24–86) with male comprising 64.0%. MMR-D was found in 4.4% (n = 24) and associated with age ≥ 65 (50% vs 29.9%; P = 0.037), antrum-origin (62.5% vs 34.1%, P = 0.004) and well/moderately-differentiated histology (41.7% vs 25.8%, P = 0.110). According to our prognostic model (Koo DH et al, 2011), MMR-D pts were less likely to be classified into poor-risk group (4.2% vs 16.8%, P = 0.102). In good-risk group, MMR-D pts had significantly shorter PFS (6.0 vs 9.0 months, P = 0.045) and OS (10.1 vs 20.9 months, P = 0.047), while pts in moderate and poor risk group showed no difference in survival depending on MMR status. Conclusions: MMR-D GC showed significantly shorter PFS and OS on F-P doublet in good-risk pts and further investigation is needed to determine underlying molecular mechanisms. With the negative impact of MMR-D on the effect of cytotoxic chemotherapy, exclusion of MMR-D pts should be considered in future trials of ICI and cytotoxic chemothrapy combination.
Comprehensive molecular profiling of IDH1/2 mutant biliary cancers (BC).
Authors: Battaglin Francesca , Xiu Joanne , Baca Yasmine , Shields Anthony Frank , Goldberg Richard M. , Seeber Andreas , Habib Diane , Soni Shivani , Puccini Alberto , Tokunaga Ryuma , Arai Hiroyuki , Wang Jingyuan , Berger Martin D. , Astsaturov Igor A. , Lockhart Albert Craig , Zhang Wu , Marshall John , Korn W. Michael , Lenz Heinz-Josef , El-Khoueiry Anthony B.
Published: February 2020

479

Background: Isocitrate dehydrogenases (IDH) play a key role in energetic metabolism and IDH mutations (mut) promote oncogenesis via epigenetic and genetic changes. Data addressing the molecular contexture of IDH1/2 mut in BC are lacking. We aimed to characterize the molecular profile of IDH1/2 mutant (mIDH) GI cancers with a focus on BC. Methods: 27954 GI cancer samples collected between August 2000 and July 2019 were included: 2057 BC (1159 ICC, 277 extrahepatic CC, 573 gallbladder, 48 unspecified CC), 13807 colorectal, 4183 gastric/esophageal, 3060 other. Samples were analyzed using NextGen DNA sequencing, in situ hybridization, RNA sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mut. MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Results: mIDH frequency in BC was 10.3% (211/2057), with higher prevalence of IDH1 mut (8.2%). ICC showed the highest mut prevalence: IDH1 13.5%, IDH2 4%. Mut rates in other GI cancers types were < 1%, except for HCC (1.9%, 11/582) and small bowel (1.1%, 8/736). When compared to IDH wild type (WT), mIDH BC showed lower mut rates in TP53 (13 vs 43%), KRAS (8 vs 19%), CDKN2A (1 vs 9%), and SMAD4 (0 vs 9%), whereas PBRM1 mut were higher (14 vs 5%) ( P < .001 for all comparisons). There was a trend towards higher frequency of ARID1A and BAP1 in mIDH BC. HER2 expression and amplification rates were lower in mIDH vs WT BC (0.5 vs 3%, P = .048 and 0 vs 6%, P = .002). FGFR2 fusion was detected in 7% of WT vs 2% of mIDH BC. mIDH BC showed a lower TMB (0.7 vs 3.7%, P = .048) and a trend for lower MSI rates (0.6 vs 3%, P = .06) vs WT BC. Conversely, IDH mut were associated with higher TMB and MSI ( P < .001) and higher PD-L1 expression in other GI cancers. Conclusions: This is the largest and most extensive profiling study to investigate the molecular makeup of mIDH BC and GI tumors. Our data show distinct gene alteration patterns characterizing mIDH BC, involving genes related to chromatin remodeling and DNA repair, and a differential expression of immune related markers compared to other mIDH GI tumors. These findings can contribute to the development of rational combination therapies and to improved patient selection in the future.
CheckMate 459: Health-related quality of life (HRQoL) in a randomized, multicenter phase III study of nivolumab (NIVO) versus sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: Edeline Julien , Yau Thomas , Park Joong-Won , Kudo Masatoshi , Han Kwang-Hyub , Mathurin Philippe , Merle Philippe , Finn Richard S. , Müller Tobias , Taylor Fiona , Greenwood Mike , Begic Damir , Tschaika Marina , Yip Christine , Pranschke Emma , Cocks Kim , Thompson Gwilym , Blum Steven I , Wisniewski Tami , Sangro Bruno
Published: February 2020

483

Background: SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to help improve or maintain HRQoL. This phase 3 study compared HRQoL of NIVO vs SOR as 1L therapy in pts with aHCC as an exploratory endpoint. Methods: FACT-Hep was administered cycle 1, day 1 and every other cycle. The effect of NIVO vs SOR on HRQoL using FACT-Hep was assessed via repeated measures mixed models (MMRM). Kaplan–Meier curves and Cox proportional-hazards models determined between-treatment differences in time to first and time until definitive deterioration (TTD/TUDD) based on prespecified thresholds for minimally important differences. The GP5 item from FACT-Hep was used to assess the burden associated with treatment side effects. Results: 743 pts with aHCC were randomized to NIVO (n = 371) or SOR (n = 372). Median OS was 16.4 mo for NIVO, 14.7 mo for SOR (HR 0.85 [95% CI 0.72–1.02]; P = 0.0752). ORR was 15% for NIVO, 7% for SOR (OR 2.41 [95% CI 1.48–3.92]). HRQoL scores were completed at baseline by 94.6% and 92.5% of participants, respectively, and were similar (FACT-Hep total: NIVO 140.7 [SD 21.5] and SOR 140. 6 [SD 19.1]. Questionnaire compliance rates exceeded 70% at most visits. MMRM analyses yielded clinically meaningful and statistically significant least squares means differences favoring NIVO on FACT-Hep total (10.1 [95% CI 7.3–13.0]), physical well-being (PWB; 2.0 [95% CI 1.4–2.6]), and functional well-being (FWB; 2.5 [95% CI 1.7–3.2]) scores. No sub-scales favored sorafenib. TTD was significantly delayed in NIVO for FACT-Hep total (HR 0.62 [95% CI 0.51–0.74]), PWB (HR 0.62 [95% CI 0.52–0.74]), FWB (HR 0.73 [95% CI 0.61–0.88]), and hepatobiliary cancer subscale (HR 0.57 [95% CI 0.48–0.69]). TUDD results were consistent with TTD. A greater proportion of NIVO pts did not experience increased burden of side effects (50%–67.7%) compared with SOR (26.8%–45%) based on the GP5 item. Conclusions: These patient-reported findings demonstrate that pts taking NIVO had superior HRQoL and reduced side effect burden, further supporting clinical data showing a treatment benefit for 1L NIVO in aHCC. Clinical trial information: NCT02576509.
Treatment of metastatic colorectal cancer (mCRC) according to age.
Authors: Ortega Laura , Torres Pérez-Solero Gabriela , Arregui Valles Marta , Alva Bianchi Manuel , Aparicio Salcedo Inmaculada , García González Gonzalo , Gallego Gallego Iria , Muñoz Martín Andres J. , Calvo Ferrándiz Aitana , Blanco-Codesido Montserrat , Martin Miguel , Garcia-Alfonso Pilar
Published: February 2020

49

Background: Elderly patients with mCRC are underrepresented in clinical trials. For this reason, the optimal treatment in this population is uncertain. The aim of this study is to compare efficacy and safety outcomes in patients with mCRC treated in our institution according to age (<65 vs ≥65 years). Methods: We conducted a retrospective analysis of 482 patients with mCRC attended in the Hospital Gregorio Marañón (Spain) between January 2010 and 2018. Results: Patients characteristics table. First-line: chemotherapy (CT) 98.7% vs 97.3% respectively (p=0.324), biologic agents (BA) 81.2% vs 79.0% (p=0.585). Significantly more <65-year-old patients received FOLFOX (60.5% vs 44.4%) and more ≥65-year-old patients XELOX (9.2% vs 17.5%) or capecitabine (2.0% vs 7.5%). Second-line: CT 64.9% vs 63.5% (p=0.764), BA 60.4% vs 51.1% (p=0.055). Significantly more <65-year-old patients received FOLFIRI (67.0% vs 54.5%) and more ≥65-year-old patients irinotecan (2.0% vs 8.6%). Third and subsequent lines: Significantly more young patients received a third-line (CT: 41.6% vs 31.0%; BA: 24% vs 21.6%), fourth-line (CT: 22.1% vs 11.9%; BA:16.2% vs 6.4%) and fifth-line of treatment (CT: 11.7% vs 5.8%; BA: 4.5% vs 3.6%). More young patients underwent metastasis resection (74.0% vs 58.1%, p=0.001). There were no differences in rate of post-operative complications (p=0.840). There were no differences in overall survival (36.05m vs 28.06, p=0.142), progression-free-survival (first-line: 12.73m vs 11.78m, p=0.139; second-line: 8.78m vs 62.71m, p=0.254) or adverse event rate (73.4% vs 73.6%, p=0.967). Conclusions: Intensive treatment could be an effectiveness and safe option in selected elderly patients.

[Table: see text]
Hepatic adverse events during treatment with immune checkpoint inhibitors (ICI) in cancer patients: A territory-wide patient cohort study.
Authors: Chan Stephen Lam , Yip Terry Cheuk-Fung , Wong Vincent Wai-Sun , Chan Anthony W.H. , Tong Cathy Ka Kiu , Tse Yee Kit , Yuen Becky Wing-Yan , Luk Hester Wing-Sum , Lui Grace Chung-Yan , Chan Henry L.Y. , Mok Tony S. K. , Wong Grace Lai-Hung
Published: February 2020

508

Background: Hepatic adverse events (AEs) are commonly encountered during ICI treatment in cancer. We evaluated the incidence and impact of hepatic AEs in a territory-wide cohort of 1509 patients who received ICI for cancer treatment. Methods: This is a territory-wide retrospective observational cohort study in Hong Kong. We identified patients through the regional hospital database (CDARS), based on the drug record of ICIs from 1 Jan 2014 to 31 Oct 2018. Serial liver functions before, during and at 3-month after ICI, were retrieved. Hepatic AEs were graded according to CTCAE 4.0. Results: The mean age was 60 years and 65.4% were male with the commonest malignancies being lung cancer (37.0%), liver cancer (17.0%) and gastrointestinal (GI) cancer (8.4%). Grade 1-2 and grade 3-4 hepatic AE occurred 39.8% and 23.3% of patients, respectively, during or within 3 months after ICI. During ICI, 39.5% developed grade 1-2 and 13.0% had grade 3-4 hepatic AE. The most common manifestations of hepatic AE occurred as elevation of ALT/AST (grade 1-2: 38.7%; grade 3-4: 10.3%). The median time of duration from ICI 1st dose to hepatic ≥ Grade 3 AE was 54 days (IQR: 22-124). Patients with liver cancer were more likely to develop hepatic AE (grade 1-2: 37.4%; grade 3-4: 55.5%). In all patients and cancer subgroup, patients with grade 3-4 hepatic AE had worse OS than grade 1-2 hepatic AE (Table). Conclusions: Hepatic AE occurs in more than half of the patients receiving ICI, with over 20% being grade 3-4 AE. Regardless of tumor types, development of hepatic AE during ICI is associated with poor prognosis.

[Table: see text]