bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-tailored FOLFIRINOX in the first-line treatment of patients (pts) with advanced pancreatic cancer (PC).
Authors: Ulusakarya Ayhan , Teyar Nahla , Karaboue Abdoulaye , Haydar Mazen , Krimi Sarra , Biondani Pamela , Gumus Yusuf , Almohamad Watek , Morere Jean-Francois
Published: January 2019

499

Background: FOLFIRINOX is an effective reference regimen in the 1st line treatment of advanced PC, despite its high level of toxicity. We report recent data from pts treated with this regimen at Paul Brousse university hospital. Methods: From January to December 2016, 37 pts with advanced PC received patient-tailored FOLFIRINOX as 1st line intent to treat chemotherapy. The first 1 to 3 courses were administered without irinotecan if initial serum bilirubin was ≥ 1.5 x upper limit of normal. Oxaliplatin was stopped for severe sensory neuropathy. Initial dose reductions were made according to pt profile (e.g., age, comorbidity) and later due to toxicity. The treatment was continued until surgery or disease progression. Endpoints were time to progression (TTP), overall survival (OS), objective response rate (ORR) and secondary complete resection (R0R1). Results: There were 22 male (59%) and 15 female pts (41%) aged 44 to 81 years (median: 64). They had locally-advanced (18 pts, 49%) and metastatic PC (19 pts, 51%). PC was head, body, tail located in 24 (65%), 8 (22%) and 5 pts (14%) respectively. Biliary stent was placed in 22 pts (59%). Pts had a performance status (PS) of 0 (60%) or 1 (40%). Median treatment duration was 20 weeks for oxaliplatin, 22 weeks for irinotecan, 23 weeks for 5FU. At the cut-off on April 27th 2017, protocol was ongoing for 11 pts (30%). Median number of cycles was 9 (2-20). Median dose intensity was 29 mg/m2/w for oxaliplatin, 57 mg/m2/w for irinotecan and 886 mg/m2/w for 5FU. We observed 4 CR (11%), 12 PR (32%), 12 SD (32%) and 5 PD (14%). Four pts were not evaluable. ORR was 43%, disease control rate 75%, 11 pts (30%) underwent R0R1 resection. After a median follow-up of 8 months (1 - 16), median TTP and OS were not reached. TTP was associated with body location (HR = 3.5 [95% CL, 1.1-11.0], p = 0.033) and disease stage (HR = 10.5 [2.2-49.5], p = 0.003), a trend was observed with biliary stent placement (HR = 0.4 [0.1-1.1], p = 0.067). Conclusions: Modified FOLFIRINOX with patient-tailored dose adaptations seems to offer better results in pts with advanced PC compared with classic FOLFIRINOX. This strategy deserves prospective evaluation to further improve clinical outcomes in the management of advanced PC.
Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing.
Authors: Lin Jianzhen , Shi Weiwei , Zhao Songhui , Hu Jinwei , Hou Zheng , Yao Ming , Chrin Gungwei , Pan Jie , Hu Ke , Zhao Lin , Javle Milind , Wang Kai , Zhao Haitao
Published: January 2019

500

Background: Lenvatinib (Len) is a multikinase inhibitor targeting VEGFR 1-3, FGFR 1-4 and other kinases. Pembrolizumab (Pem) and nivolumab (Nivo) are antibodies inhibiting programmed cell death 1 (PD-1) and reactivate T-cell cytotoxic effect. Len plus PD-1 inhibitors have shown promising results in treating various solid tumors. The role of this combination in ICC is undefined. Methods: 14 ICC pts (median age 49 years, range 34-68; 7 males and 7 females) with treatment of enrolled in a single center, observational study of Len plus Pem/Nivo. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were measured according to RECIST 1.1. Next generation sequencing (NGS) with deep coverage on 450 cancer genes and whole exome sequencing were performed in 7 pts to detect all classes of genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results: All 14 pts had > = 2 prior anticancer therapy with clinical stage IV. ORR was 21.4% with 3 pts achieved partial response (PR), DCR was 92.9% and clinical benefit rate (ORR + durable stable disease > = 5 months) was 64.3%. Median PFS was 5.9 months (95% CI: 4.2-6.2). The most common adverse events (AEs) included hypertension, aminotransferase elevation and fatigue. The grade-3 AEs were occurred at 14% while no grade-4 AE was observed. The most altered genes in the 7 sequenced tumors were IDH1 (3 pts), ARID1A (3 pts), PIK3CA (3 pts), TP53 (2 pts) and BAP1 (2 pts). 4 out of the 7 pts had high TMB ( > 12 mut/Mb) and all responded to Len plus Pem/Nivo with 2 PR. One pt with low TMB and FGFR2 mutation had a response of 27% decreased target lesion. Two low TMB pts were progressed, including one with FGFR2 rearrangement. A responder harbored a 399 bp deletion on MLH1, and was identified as MSI-H. More data will be presented. Conclusions: Our study preliminarily indicates that combining Len with PD-1 inhibitors results in promising efficacy in advanced ICC. High TMB from 450-gene NGS panel was strongly associated with a better therapeutic response.
Economic analysis of transarterial chemoembolization (TACE) versus stereotactic body radiotherapy (SBRT) for the treatment of hepatocellular carcinoma (HCC).
Authors: Nugent Francis W. , Packard Amy , Hunter Klaudia , Qamar Amir , Stuart Keith E. , Gunturu Krishna , Flacke Sebastian , Molgaard Christopher , Iqbal Shams , Gordon Fredric
Published: January 2019

508

Background: For HCC patients undergoing liver transplantation (LT), local treatment as a "bridge" is standard to decrease tumor burden. The most common treatment is TACE, but the best and cheapest bridging modality is unclear. We prospectively compared SBRT to TACE as a bridge for HCC patients undergoing LT. We then compared the cost of the two strategies. Methods: From 9/2014-1/2017, 31 patients within Milan Criteria with C-P Class A/B cirrhosis were randomized to TACE vs. SBRT. TACE patients received 2 treatments one month apart utilizing DEBDOX beads (n = 17) and were hospitalized for symptom management. Patients receiving SBRT (n = 14) received outpatient treatment comprising 5 fractions of radiation using fiducials. Using EPSI, the institutional cost accounting and clinical data base, all patients treated were analysed. Financial and cost data was used to calculate the average contribution margin (total payment minus direct cost) for each type of treatment and then multiplied for each patient by the number of treatments involved. Results: See table. Conclusions: SBRT costs less than TACE to treat HCC. Given reduced reimbursement for hospitalizations post-TACE, additional opportunity costs may be available at given institutions depending on bed availability. Clinical trial information: NCT02182687. [Table: see text]
Analyzing the efficacy and safety of immunotherapy in pancreatic ductal adenocarcinoma (PDA): A systematic review and meta-analysis.
Authors: Babiker Hani M. , Zahid Umar , Howe Carol L. , Scott Aaron James , Riaz Irbaz Bin , Elliott Cynthia M , Acharya Utkarsh H , Recio Boiles Alejandro , Elquza Emad , Mahadevan Daruka
Published: January 2019

512

Background: The tumor microenvironment in PDA is heterogeneous and immunosuppressive given the presence of regulatory T cells and exhausted effector T cells. Despite the upsurge of effective immunotherapeutic agents (IA) in other tumor types, the role in PDA remains unknown. We conducted a meta-analysis of IA in PDA. Methods: Following PRISMA guidelines, we searched PubMed/MEDLINE, Elsevier/Embase, Wiley/Cochrane Library and ClinicalTrials.gov. Articles were selected per the following criteria: (1) Study participants had a diagnosis of PDA; (2) An IA was used in the trial. Titles, abstracts and full text articles were reviewed by 2 independent reviewers; disagreements were resolved by a third. Data extraction and analysis were performed by 3 independent reviewers. Descriptive analysis, mean, median, confidence interval and forest plots were used for statistical analysis. Results: We found 20,792 studies through the database, 16,105 remained after duplicates were removed and 15,889 were excluded due to irrelevance. Strict inclusion criteria were applied to the full text of 216 articles. The most common reason for exclusion were conference abstracts (44%) and ongoing trials (16%). Fifty-four trials (39 metastatic (met), 12 adjuvant (Ad) and 3 neoadjuvant (nAd) met criteria for further analysis. Age range was 27-86 (median 61) and 52.3% were males. IA included cytokine therapy (33%), peptide vaccines (22%), dendritic cell vaccine (13%), oncolytic viruses (9%), CTLA-4 inhibitors (2%) and others. IA in met-PDA had a median overall survival (mOS) of 8.1 months (ms) and a disease control rate (DCR) of 55.4% (95% CI, 51.85-58.95). There was no statistical difference in DCR among IA subtypes (range 49-60%) (p = 0.22). The mOS of Ad-PDA trials was 25 ms (historically comparable to gemcitabine, p = 0.75) and 18 ms for nAd-PDA. The most common Gr1/2 toxicities were skin reactions, fever, and chills and Gr3/4 were cytopenias, diarrhea, and mucositis. One death occurred due to neutropenic sepsis. Conclusions: IA demonstrates modest efficacy in the treatment of met-PDA albeit exhibits a favorable toxicity profile. Many trial results are available only in abstract format and some are ongoing.
Metastatic gastroenteropancreatic neuroendocrine tumors treated with somatostatin analogues: Ten years experience in a third level hospital in Mexico City.
Authors: Pimentel Alberto , Dip Borunda Abdel Karim , Bueno Rosario Luis Jonathan , Martinez Gloria Martinez , Pluma Miguel Angel , Quintana Miguel , Silva Juan ALEJANDRO , Rivera Samuel
Published: January 2019

514

Background: Gastroenteropancreatic neuroendocrine tumors (GEP NET´s) are infrequent tumors, with a variety of symptoms depending of the kind of peptide they secrete as well as the affected organs. Long acting somatostatin analogues have shown an adequate rate of symptom control in functional tumors, they also have demonstrated antiproliferative effect, which is translated in a significant improvement of progression free and overall survival Methods: In this retrospective analysis of patients with metastatic GEP NET treated with long acting somatostatin analogues as first line, treated between 2005 and 2015, we evaluated clinical and pathological features, symptoms, disease control and survival adjusted with OMS classification Results: Our cohort included 95 patients with a mean age of 53 years. Primary affected sites were midgut (29.4%), followed by pNET (17.%), stomach (14.7%), and primary unknown in 14%. 20% of cases were functional tumors with diarrhea as the most common symptom in 70% and flushing in 50%. Considering the whole cohort the most prevalent symptom was abdominal pain in the 50% of cases. The OMS classification showed low grade tumors in 65% and 35% intermediate grade. Most common metastatic organ sites were; liver only 35%, liver and other 30%, peritoneum 10% and lymph nodes in 6%, non-specified sites in 19%. Somatostatine analogues used in first line were octreotide in 80% and lanreotide in 20%. Survival results demonstrated a progression free survival for the whole cohort of 84months. No differences between lanreotide and octreotide were observed. Conclusions: This study represents the first Mexican cohort of patients with GEP NET’s treated with somatostatin analogues with a long follow up.
Management of carcinoid syndrome (CS): A systematic review of systemic treatment options.
Authors: Wolin Edward M. , Benson Al Bowen
Published: January 2019

516

Background: CS is a major cause of symptom burden (diarrhea/flushing) in patients (pts) with neuroendocrine tumors and is associated with shortened survival and severe complications such as carcinoid heart disease. We performed a systematic review of clinical evidence for CS systemic treatments. Methods: PubMed, Embase, and Cochrane databases were searched. Large ( > 60 pt) prospective clinical trials investigating the efficacy/safety of systemic treatment options for pts with CS were eligible for inclusion. Data extracted included study design, pt population, interventions, prior treatments, permitted concomitant medications, study endpoints/statistical analyses, and efficacy/safety outcomes. Results: Six large prospective clinical trials (total 953 pts) were identified from 144 search results. Significant heterogeneity existed in pt populations, control groups (placebo vs active comparator), duration of therapy, study endpoints, and efficacy/safety data reporting. Interventions assessed were long-acting and subcutaneous octreotide (OCT & OCT SC), lanreotide (LAN), telotristat ethyl (TE)+somatostatin analogues (SSA), pasireotide (PAS), and everolimus (EVE)+OCT. Symptom response was variably assessed by the frequency of diarrhea/flushing and/or receipt of rescue short-acting SSA in 5/6 studies; a significant improvement in at least one of these measures occurred in 4 studies (OCT and OCT SC; LAN; TE+SSA). Failure to meet symptom response criteria ranged from 29-82% in the studies. Reported reductions in CgA and/or 5-HIAA reached statistical significance in 3 studies (LAN; EVE+OCT; TE+SSA). Interventions were generally well tolerated. Two phase 3 trials focused specifically on management of CS symptoms refractory to SSA; strategies included switching to PAS or an increased dose of OCT (40 mg q28d) for refractory diarrhea/flushing, or receipt of TE with continued SSA for refractory diarrhea. Conclusions: SSA provide substantial symptom relief for pts with CS. For refractory symptoms, TE can be added, SSA dose increased, and metastasis debulking can be used (with surgery, hepatic artery embolization, ablation, and PRRT). The addition of biologic agents to SSA can further improve CS management.
Quantitative PET-MRI for early treatment response assessment in pancreatic ductal adenocarcinoma.
Authors: Consunji Martin Valera , Behr Spencer , Ko Andrew H. , Tempero Margaret A. , Cinar Pelin , Wang Zhen J.
Published: January 2019

520

Background: There is an unmet need for improved non-invasive markers to assess early treatment response in pancreatic ductal adenocarcinoma (PDAC). Assessing early treatment response using tumor size on anatomic imaging or serum carbohydrate antigen 19-9 (CA19-9) level is unreliable. In contrast, metabolic and functional imaging is a promising new tool that may differentiate responders from non-responders early on during therapy. Therefore, the objective of this pilot study was to explore the potential of integrated positron emission tomography-magnetic resonance imaging (PET-MRI) to provide imaging biomarkers of early (4 weeks post treatment initiation) response in patients with advanced PDAC. Methods: 13 patients with biopsy-proven locally advanced or metastatic PDAC underwent integrated 18F-fluorodeoxyglucose PET-MRI through the abdomen prior to, and again at 4 weeks post, treatment initiation. Patients also had computed tomography (CT) imaging of the chest, abdomen, and pelvis and serum CA19-9 levels measured, as per standard of care. Patients were classified as responders or non-responders according to RECIST (Response Evaluation Criteria In Solid Tumors) on delayed CT, at 8-12 weeks interval post treatment initiation. Changes in metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from PET, and apparent diffusion coefficient (ADC) from diffusion-weighted MRI at 4 weeks were compared between responders and non-responders. Results: Of the 13 patients, there were 7 responders (partial response by RECIST) and 6 non-responders (progressive or stable disease by RECIST). After 4 weeks of therapy, responders had a significantly greater decrease in MTV (p = 0.003) and TLG (p = 0.006) compared to non-responders. Responders also had a significantly greater increase in mean and minimum ADC (p = 0.004 and p = 0.024, respectively) compared to non-responders. Change in tumor size at 4 weeks was not significantly different between responders and non-responders (p = 0.11). Conclusions: Integrated PET-MRI can provide early assessment of treatment response in patients with advanced PDAC.
Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer.
Authors: Yamada Suguru , Fujii Tsutomu , Takano Nao , Takami Hideki , Suenaga Masaya , Niwa Yukiko , Hayashi Masamichi , Iwata Naoki , Kanda Mitsuro , Kobayashi Daisuke , Tanaka Chie , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: January 2019

523

Background: Gemcitabine plus nab-paclitaxel (GnP) treatment is recommended for metastatic pancreatic adenocarcinoma (PDAC), and has been widely spread in our clinics. However, the usefulness for the patients with locally advanced PDAC is still controversial. We designed the phase I study to assess the toxicity and decide the recommended dose based on dose-limiting toxicity (DLT) of concurrent chemoradiotherapy using GnP for unresectable locally advanced (UR-LA) PDAC. Methods: UR-LA PDAC patients were enrolled in this clinical trial. The patients received the GnP on days 1, 8 and 15 every 28 days, and the cycles were repeated until PD. The patients were scheduled to receive gemcitabine (mg/m2) and nab-paclitaxel (mg/m2) at 5 dose levels: 400/75 (level 0), 600/75 (level 1), 600/100 (level 2), 800/100 (level 3) and 800/125 (level 4). Radiation therapy was delivered as a total dose of 50.4 Gy in 28 fractions, 1.8Gy per day. DLT was defined as grade 4 leucopenia or neutropenia ≥ 3 days, grade 3 neutropenia with fever ≥ 38℃, grade 3 or 4 thrombopenia, grade 3 non-hematological toxicity and > 14 days delay of treatment. Response and disease control rate, safety, adverse events, PFS and OS were evaluated. Results: Twelve patients were enrolled in this study. Treatment was well tolerated, and every 12 patients completed radiotherapy of 50.4 Gy. Our recommended dose was level 3, gemcitabine 800 mg/m2 and nab-paclitaxel 100 mg/m2. One patient experienced the DLT. The response rate was 41.7% and disease control rate was 75% (PR: 5, SD: 4, PD: 3). Median OS was 9.0 months. Among 12 patients, 6 (50%) patients underwent conversion surgery, and the pathological CR was observed in 2 patients. Conclusions: The concurrent chemoradiotherapy using GnP for UR-LA PDAC can be delivered safely and the high rate of conversion surgery was observed in our clinical trial. Based on this results, we will proceed the phase-II study. Clinical trial information: UMIN000020475.
Identification of a novel molecule target for the diagnosis, prediction, and treatment of hepatic metastasis of gastric cancer.
Authors: Kanda Mitsuro , Tanaka Haruyoshi , Miwa Takashi , Kobayashi Daisuke , Tanaka Chie , Takami Hideki , Hayashi Masamichi , Iwata Naoki , Niwa Yukiko , Yamada Suguru , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: January 2019

53

Background: Hepatic metastasis of gastric cancer has become a growing issue, because effective treatment and specific biomarkers are not available. The aim of this study was to identify a molecule mediating hepatic metastasis, which serves as a diagnostic marker, and to determine its potential as a therapeutic target. Methods: Stable knockdown gastric cancer cells were established using genome editing technique and cell activities were compared to control cells in vitro and in vivo. Tissue expression levels of the candidate molecule were evaluated in 300 patients with gastric cancer and correlated to clinicopathological parameters including patterns of metastasis and recurrences. Results: Global expression analysis revealed that synaptotagmin VII (SYT7) was overexpressed in gastric cancer tissues with hepatic metastasis. Gastric cancer cell lines differentially expressed high levels of SYT7 that positively correlated with those of SNAI1 and TGFB3, and inversely with RGS2. Stable knockout of SYT7 inhibited the proliferation of gastric cancer cells, indicated by increased apoptosis, and decreased cell migration, invasion, and adhesion abilities. The tumorigenicity of SYT7 knockout cells was moderately reduced in a mouse subcutaneous model and more strikingly decreased in a hepatic metastasis model. The protein expression levels of BCL2 and HIF1A were decreased in tumors formed by SYT7 knockout cells, and SYT7 levels in primary gastric cancer tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. Conclusions: SYT7 serves as a target for treating hepatic metastasis of gastric cancer as well as a diagnostic tool.
A randomized phase 2 study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with metastatic or unresectable gastrointestinal stromal tumor (GIST).
Authors: Singh Arun S. , Chmielowski Bartosz , Hecht J. Randolph , Rosen Lee S. , Wang Xiaoyan , Brackert Sandra , Adame Carlos R. , Linares Paulina J , Schink Elena , Marubio Lisa Marie , Eilber Frederick C.
Published: January 2019

55

Background: The therapy with tyrosine kinase inhibitors changed the prognosis of patients with advanced GIST. Unfortunately, most of the tumors become resistant to therapy and patients succumb to the disease. New therapies for this patient population are needed. Here we report interim analyses of safety and efficacy in advanced GIST patients treated with immunotherapy. Methods: Patients with advanced/metastatic GIST progressing on at least imatinib were enrolled on a randomized, parallel group, unblinded phase 2 trial of either nivolumab(nivo) (240 mg Q2wks) or nivo (240 mg Q2wks) with ipilimumab(ipi) (1mg/kg Q6wks) for up to 2 years. The primary endpoint was the objective response rate (ORR) of nivo alone or nivo + ipi by RECIST 1.1 criteria. Patients were randomized 1:1 and the response was assessed every 8 weeks. With a sample size of 20 per group, an exact binomial test with a nominal 0.050 one-sided significance level will have 82% power to detect the difference between the null hypothesis response rate 1.5% and the alternative response rate of 15%. Secondary objectives are to ascertain the PFS, CBR, RR by Choi criteria and safety. Blood and biopsies are also being collected. Results: To date, 14 patients (median # of prior therapies: 4) have started on trial and 8 remain on treatment. In the nivo only arm, 3/7 patient had SD for a CBR of 42.8 %. The median PFS of the nivo arm was 8 weeks. In the nivo + ipi arm, 1/5(20%) patients had a PR and 1/5 have SD for a CBR of 40%; 2 patients were censored. The median PFS of the nivo + ipi arm was 8.43 weeks. 1 patient in the nivo arm had grade 3 fatigue and 1 patient in the nivo + ipi arm had grade 3 diarrhea. Pretreatment biopsies have been obtained in all patients and blood has been collected on all patients for correlative analysis. Conclusions: In a heavily pretreated GIST population, durable responses and disease control were observed. To date, the drugs have been well tolerated and no new safety signals have been observed in this disease state. Clinical trial information: NCT02880020.
SCOT: Tumor sidedness and the influence of chemotherapy duration on DFS.
Authors: Saunders Mark P. , Paul James , Crosby Jana , Brown Gordon , Iveson Timothy , Kerr Rachel , Harkin Andrea , Allan Karen , McQueen John , Pearson Sarah R , Cassidy James , Medley Louise C. , Raouf Sherif , Harrison Mark , Brewster Alison , Rees Charlotte , Ellis Richard , Thomas Anne L. , Churn Mark , Maka Noori
Published: January 2019

558

Background: Patients with R-sided tumours who develop metastatic disease have a worse prognosis compared to patients with L-sided tumours. The latter may also have a greater benefit from treatment with EGFR inhibitors. In general, registry studies and meta-analyses have shown that patients with loco-regional R-sided tumours have a worse overall survival (OS). This has recently been confirmed by the PETACC8 study but only after they had relapsed. There was not a significant difference in disease free survival (DFS). Methods: The SCOT study showed that 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) was non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. Here we divide the population into left and right-sided tumours to see whether sidedness had an impact on DFS. We also evaluated whether sidedness impacted on the 3 vs. 6-months comparison in SCOT. Results: 6088 patients with Stage III/high risk Stage II cancers or the colon or rectum were randomised between March 27, 2008 and November 29, 2013 from 244 centres (164 UK, 32 Australia, 19 Spain, 14 Sweden, 10 Denmark and 5 New Zealand). In February 2017 (3-years FU) information on sidedness was available for 3219 patients (1207 R-sided, 2012 L-sided). Characteristics: Right: median age: 65, Male: 53%, T4 41%, Stage II: 17%; Left: median age: 65, Male: 66%, T4 24%, Stage II: 21%). Patients with R-sided tumours had a significantly worse DFS (3-year DFS right: 73% (se=1%), left: 80% (se=1%). HR 1.401 (95% CI 1.216-1.615; p=0.000004). Adjusting for T and N-stage reduced the HR to 1.215 (95% ci 1.051-1.404, p=0.009). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR (3 month/6 month) 1.049 (0.849 -1.296) L: 0.910 (0.753-1.099). Test for homogeneity, p=0.327). Further sub-set analysis was limited due to cohort size. Conclusions: This is the first study to show that unselected patients with R-sided tumours had a worse DFS compared to L-sided tumours. This implies that prognosis is influenced primarily by greater recurrence rather than the contributing factors that influence OS. Tumour sidedness did not impact on the 3-months vs. 6-months comparison in SCOT. Clinical trial information: ISRCTN59757862.
Effect of PET-CT on disease recurrence and its management in patients with potentially resectable colorectal cancer liver metastases: The long-term results of a randomized control trial.
Authors: Serrano Aybar Pablo Emilio , Gu Chu-Shu , Husien Mohamed , Jalink Diederick , Martel Guillaume , Tsang Melanie E. , Hallet Julie I. , Gallinger Steven , Ritter Anne , McAlister Vivian , Sela Nathalie , Solomon Hannah , Beyfuss Kaitlyn , Li Christine , Lee Erika , Moulton Carolanne , Levine Mark Norman
Published: January 2019

562

Background: The PETCAM randomized trial evaluated the effect of preoperative PET-CT (vs. no PET-CT) on surgical management in patients with colorectal cancer liver metastases. In this study, 8% of patients had a change in surgical management, including a higher proportion of major liver resections in the PET-CT arm. The current study compares the intervention groups for 5-year disease free (DFS) and overall survival (OS), and evaluated their long-term clinical course, i.e. sites of recurrence and management of disease recurrence. Methods: Recruitment to the trial occurred between 2005-2010, with last follow-up in 2013. Data on recurrence, management of recurrence and mortality from 2013-2017 was collected from patient’s charts. Recurrences according to site and management were described. Cox proportional Hazard Models were used to calculate the risk for recurrence and death. OS was calculated with Kaplan-Meir method and compared with log-rank test. Results: At 5 years, 157 of 404 (39%) patients were still alive and 19 patients were lost to follow-up. Median follow-up is 4.2 years. There were no differences in DFS (HR: 1.12, 95%CI: 0.88-1.42) or OS (HR: 0.97, 95%CI: 0.74-1.28) between groups. The median DFS for the 372 patients who had surgery was 17 months, 95%CI: 14.7-19.4. Risks factors for recurrence were: extrahepatic disease, liver tumour size, and nodal stage. The median OS for all patients was 50 months, 95%CI: 43.5-64.3. Risks factors for death also included age and prior use of chemotherapy. During the follow-up period, 287/404, 71% patients recurred (mostly liver and lung); 137 (48%) were treated solely with chemotherapy and 35% were treated with surgery with curative intent. Of these, the majority recurred (109/116, 94%). The median OS following first recurrence was 27.5 months, 95%CI: 23-30. Conclusions: PET-CT did not improve DFS or OS. Survival following liver resection is similar to previous reports, however most patients experience disease recurrence. A substantial proportion of patients who recur undergo surgery, however it is likely that they will recur again.
Utilization of imaging modalities in the staging of newly diagnosed rectal cancer: A survey of U.S. radiation oncologists.
Authors: Yahya Jehan , Farrell Matthew , Herzig Daniel , Degnin Catherine , Chen Yiyi , Holland John M. , Brown Simon , Jaboin Jerry Jeff , Thomas Charles R. , Mitin Timur
Published: January 2019

564

Background: Accurate staging is crucial for management of patients (pts) with newly diagnosed rectal cancer. Endorectal ultrasound (EUS) has been a commonly used imaging modality for almost two decades, with magnetic resonance imaging (MRI) now preferred by national guidelines. Routine positron emission tomography (PET) is not recommended for initial staging. The current utilization of imaging modalities by radiation oncologists (ROs) in staging newly diagnosed rectal cancer pts in the United States is unknown. Methods: We conducted an anonymous IRB-approved online survey of practicing U.S. ROs. Respondent characteristics were tested for association with self-assessed utilization of imaging modalities using Chi-squared test. Staging 75% of more rectal cancer pts with a given modality was defined as high utilization. Results: We received 220 responses from practicing U.S. ROs. Among the responders, 85 are academically affiliated and the majority specialize in treating GI malignancies, with 98 seeing more than 10 rectal cancer pts annually. Most respondents utilize all three imaging modalities for rectal cancer staging - EUS, MRI and PET/CT. Fifty two percent and 38% of respondents are high utilizers of EUS and MRI, respectively. Nearly half (47%) of respondents are high PET utilizers. High utilization of PET was associated with practice in a private setting (p < 0.05) and being within 10 years from residency training completion (p < 0.05). Conclusions: Our analysis reveals a wide discordance between national guidelines and the practice patterns among U.S. ROs, with underutilization of MRI and overutilization of PET/CT. Substantial cost savings could be realized by following national guidelines recommendations to omit the routine use of PET/CT in the initial evaluation of pts with rectal cancer.
Does metabolic health status affect the optimal starting age for colorectal cancer screening? A Korean nationwide cross-sectional study.
Authors: Choi Yoon Jin , Lee Dong Ho
Published: January 2019

573

Background: The association between metabolic syndrome and colorectal cancer (CRC) has been suggested as one of causes for the increasing incidence of CRC, particularly in younger age groups. The present study examined whether the current age threshold (50 years) for colorectal cancer (CRC) screening in Korea requires modification when considering metabolic syndrome. Methods: We examined data from the National Health Insurance Corporation database, which covers ~97% of the population in Korea. CRC risk was analyzed with stratification based on age and the presence/absence of relevant metabolic syndrome components (diabetes, dyslipidemia, and hypertension). The incidence of CRC was determined for four, 2-year time periods. Results: A total of 51,612,316 subjects enrolled during 2014-2015 were analyzed. Among them, 19.3% had diabetes, hypertension, dyslipidemia, or some combination thereof. This population had a higher incidence of CRC than did those without these conditions and this was more prominent in subjects < 40 years of age. The optimal cut-off age for detecting CRC, based on the highest Youden index, was 45 years among individuals without diabetes, dyslipidemia, and hypertension, and 62 years among individuals with at least one of these components of metabolic syndrome. Resetting the cut-off age from 50 years to 45 years achieved a 6% increment in sensitivity for CRC detection among the total population. Conclusions: An earlier start of CRC screening, namely at 45 rather than at 50 years of age, may improve secondary prevention of CRC in Korea.
Prognostic factors in patients who received surgery for colorectal cancer with peritoneal metastasis.
Authors: Furutani Akinobu , Yamaguchi Tomohiro , Kinugasa Yusuke , Shiomi Akio , Kagawa Hiroyasu , Yamakawa Yushi , Manabe Shoichi , Yamaoka Yusuke , Ogi Yusuke , Nagasawa Yoshinobu , Hino Hitoshi , Kato Shunichiro , Suzuki Takuya , Torii Kakeru , Koido Kohei
Published: January 2019

574

Background: Peritoneal metastasis (PM) in patients diagnosed with colon cancer is associated with a poor prognosis. We aimed to analyze prognostic factors associated with PM in patients diagnosed with colorectal cancer (CRC). Methods: We evaluated 237 patients who underwent surgery between 2002 and 2016 for CRC with PM. The extent of PM was evaluated using the Peritoneal Cancer Index (PCI). Clinicopathological variables, PCI score, surgical curability, and the administration of postoperative chemotherapy were evaluated. Overall survival was analyzed using the Kaplan-Meier method. Multivariate analysis was performed to assess the prognostic value of these variables, using the Cox regression model. Results: Our patients included 119 men and 118 women with a median age of 64 (range: 21–90) years. The primary tumor sites were the right-sided colon (n = 103), left-sided colon (n = 84), and rectum (n = 50). The median PCI score was 4 (range: 1–30). Synchronous PM was detected at the time of diagnosis of the primary tumor in 165 patients (69.6%). Distant metastases except peritoneal metastases was detected in 137 patients (57.8%). R0 resection was performed in 62 patients (19.0%). Postoperative chemotherapy was performed in 165 patients (69.6%). The median survival time in all patients was 19.4 (range: 0–30) months, and the five-year overall survival rate was 16.3%. Multivariate analysis revealed that PCI ≤ 5 (hazard ratio [HR]: 2.56, 95% confidence interval [CI]: 1.56-4.32, P < 0.01); the absence of distant metastasis, except peritoneal metastasis (HR: 1.65, CI: 1.15-2.40, P < 0.01); R0 resection (HR: 4.21, CI: 2.44-7.50, P < 0.01) affected the survival rate. Conclusions: Our results show that a low PCI, the absence of distant metastasis except peritoneal metastasis, and R0 resection are prognostic factors in patients diagnosed with PM-CRC.
Evolving prevalence and incidence trends of SCC of the anal canal: A SEER study.
Authors: Zhang Shunqing , DiPetrillo Thomas A. , Leonard Kara Lynne
Published: January 2019

583

Background: The incidence of squamous cell carcinoma of the anal canal (SCCA) has been rising in the last three decades. With changing patient demographics and behaviors, the trends in prevalence and incidence of the disease have changed in recent years. Methods: The Surveillance, Epidemiology, and End Results (SEER) data set from 2000 to 2014 was analyzed for trends in prevalence and incidence of SCCA and for associated demographic and tumor characteristics including stage (localized vs. regional vs. distant disease), age (20-34, 35-49, 50-64, > 65 years), and race/ethnicity (White, Black, American Indian/American Natives (AI/AN), American Pacific Islanders (API)). Results: 16,540 patients with SCCA were identified in the SEER database within the study period. The prevalence rate of SCCA was 0.01% (of 2000 standard U.S population), and the age-adjusted incidence rate of SCCA was 1.3/100,000. Prevalence and incidence was highest in patients age 50-64 and in the black population. Trend analysis of incidence demonstrated that while incidence rate continued to increase from 2000 to 2014, the average annual percentage change (APC) of incidence decreased from 4.80 before 2009 to 1.44 after. Patient population was divided into two groups: 2000-2008, with incidence of 1.6/100,000 and 2009-2014, with incidence of 2.1/100,000 (RR = 1.29, 95%CI = 1.25-1.33, p < 0.001). Incidence in the 2009-2014 group increased compared to the 2000-2008 group among all staged SCCA, patients 50 years of age and older (RR = 1.41, p < 0.001 and RR = 1.37, p < 0.001 for age groups 50-64 and > 65, respectively), and black (RR = 1.33, p < 0.001) and white (RR = 1.32, p < 0.001) race/ethnicity groups. APC in the 2009-2014 group decreased in all staged SCCA, increased in patients age 20-34, and decreased in all racial groups except AI/AN. Conclusions: There is a higher incidence and prevalence of SCCA in patients 50 years or older and in those of black ethnicity. Incidence of SCCA has increased in the US from 2000-2014, but the average APC in incidence has been decreasing except for in young patients and in those of AI/AN ethnicity. Awareness of disease prevalence and the pattern of change in incidence rate is important in the effort of disease prevention.
Can sidedness predict for survival in primary locoregional colon cancers?
Authors: Wang Weining , Seo Chin Jin , Tan Grace Hwei Ching , Chia Claramae Shulyn , Soo Khee Chee , Teo Melissa Ching Ching
Published: January 2019

584

Background: Right and left-sided colon cancers are embryonically distinct and present differently. Recently, there has been growing belief that sidedness could be independently associated with survival outcomes. This has important clinical implications regarding the prognostication, management and surveillance of colon cancer patients. Hence, we aim to investigate the impact of sidedness on survival in our patient population in this study. Methods: Patients who had primary treatment naïve colon cancer who underwent curative surgical resection in our institution from September 2002 to December 2010 were included in this study. Demographic and clinicopathological data was collected from electronic records and clinical charts. Tumours arising from the cecum, ascending colon, hepatic flexure and transverse colon were considered right-sided, while those arising from splenic flexure and descending colon were considered left-sided. Cancers of the rectosigmoid junction and rectum were excluded. Kaplan-Meier curves and log-rank test were used to compare overall, locoregional recurrence-free and distant recurrence-free survivals (OS, LRFS, DRFS respectively) between both groups. Multivariate analysis was performed using Cox regression proportional hazards. Results: 389 patients were included in this study. 238 had left-sided tumours while the remaining 151 had right-sided tumours. In our cohort, right-sided tumours were associated with older age and mucinous histology. Kaplan-Meier curves plotted showed improved LRFS in left-sided tumours (p = 0.04, median survival not reached) but no significant difference in OS and DRFS. On multivariate analysis, sidedness was also found to be an independent prognostic factor for LRFS but not OS and DRFS despite factoring in age, size of tumour, pT, pN and histology. Conclusions: Our study suggests that left-sided tumours in primary colon cancer are independently prognostic for improved locoregional survival as compared to the right-sided tumours, even after taking into account other known factors such as age, staging and histology.
Baseline characteristics as predictors of adjuvant chemotherapy (AC) discontinuations and modifications in stage III colorectal cancer (CRC) patients.
Authors: Watanabe Akie , Yang Charlie , Cheung Winson Y.
Published: January 2019

585

Background: Discontinuations and treatment modifications of AC can impact survival in CRC patients. Unfavorable baseline patient characteristics such as old age, poor ECOG performance status, and comorbidities may contribute to early treatment termination, but their precise associations with treatment interruptions are unclear. Methods: We reviewed a population-based cohort of CRC patients treated with adjuvant monotherapy (Capecitabine) or combination therapy (FOLFOX or CAPOX) within 12 weeks of curative resection in British Columbia, and determined the associations between baseline characteristics and treatment modifications (change in regimen and/or cessation of a single agent) or discontinuations. Results: Among 555 patients, median age was 66 years, 52% were men, and 16% were ECOG ≥2. In this cohort, 42% received monotherapy and 58% received combination therapy. 37% of patients had modifications to monotherapy and 31% discontinued it while 44% had modifications to combination therapy and 26% discontinued it. For monotherapy, univariate analyses showed significant associations between survival and treatment modifications ( P= 0.001) and discontinuations ( P< 0.001). Specifically, old age (≥70; P= 0.044) and pre-treatment anemia ( P= 0.016) were associated with permanent discontinuations. On multivariate analyses, non-mucinous adenocarcinoma histology predicted a higher chance of treatment modifications (OR 3.02, 95% CI 1.03-8.83, P= 0.044) while pre-treatment anemia was correlated with discontinuations (OR 2.27, 95% CI 1.14-4.50, P= 0.020). Univariate analyses of combination therapy showed a relationship between survival and discontinuations ( P= 0.005); however, only worse ECOG status (≥2) was predictive of discontinuations on multivariate analyses (OR 2.39, 95% CI 1.03-5.55, P= 0.042). Conclusions: Except for pre-treatment anemia and ECOG status, few baseline characteristics correlated with treatment modifications or discontinuations, underscoring the need for repeated clinical assessments throughout treatment. Baseline features may only be useful in deciding whether or not a patient should initiate chemotherapy.
Two-photon probes for pH: Detection of human colon cancer using two-photon microscopy.
Authors: Kim Woojung , Kim Eun Sun , Min Geeho , Kim Seung Han , Choi Seong ji , Lee Jung Min , Lee Jae Min , Choi Hyuk Soon , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Kim Chang Duck , Hong Seung Taek , Heo Jung-Nyoung , Cho Bong Rae
Published: January 2019

607

Background: In cancer cells, lysosomal pH decreases along with a concomitant increase in lysosomal volume and cathepsin expression levels. Lysosomes also play crucial roles in cancer progression following their release into the extracellular space. Since cancer cells invade a tissue by secreting degradative enzymes, the extracellular pH of tumor tissues becomes acidic. However, to date, there has been no report on the use of multi-photon microscopy (MPM) probes to image human colon cancer tissues. Methods: We have developed multi-photon (MP) pH-sensitive probes (BH-2 and BHEt-1) that exhibit absorption and emission maxima at 370 and 466 nm, and TP absorption cross-section values of 51 and 61 GM (1 GM = 10−50 cm4 s/photon), respectively, at 750 nm and pH 3.0 in a universal buffer (0.1 M citric acid, 0.1 M KH2PO4, 0.1 M Na2B4O7, 0.1 M Tris, 0.1 M KCl)/1,4-dioxane (7/ 3) solution. Results: The TPM images of CCD-18co (a normal colon cell line) and HCT116 cells (a colon cancer cell line) labeled with BH-2 were too dim to be distinguished. When the same cells were labeled with BHEt-1, however, the MPM image of the HCT116 cells was much brighter than that of CCD-18co cells, and the relative proportion of the acidic vesicles (Pacid) of the former was 5-fold larger than that of latter. BHEt-1 could also differentiate HepG2 cells (a human liver cancer cell line) from LX-2 cells (a human hepatic stellate cell line) with a 6-fold larger P acid value. Human colon cancer tissues labeled with BHEt-1 showed similar results, demonstrating much brighter MPM images and 6-fold larger Pacid values compared to normal tissue. Conclusions: These results suggest the potential utility of BHEt-1 for molecular image analysis of colon cancer tissues using MPM.
Self-monitoring and reminder text messages to increase physical activity after colorectal cancer (CRC): A pilot randomized controlled trial.
Authors: Van Blarigan Erin , Van Loon Katherine , Kenfield Stacey A. , Chan June M. , Mitchell Emily , Chan Hilary , Zhang Li , Paciorek Alan , Joseph Galen , Laffan Angela , Fukuoka Yoshimi , Miaskowski Christine , Meyerhardt Jeffrey A. , Venook Alan P.
Published: January 2019

615

Background: Over 1.3 million people in the US are living with CRC. Physical activity is associated with lower risk of CRC mortality. Interventions are needed to increase physical activity after CRC diagnosis. Methods: We conducted a pilot RCT to determine the feasibility (adherence, attrition) and acceptability of a 12-wk intervention using a Fitbit Flex™ and daily text messages to increase physical activity after CRC. Eligible patients had to have colon or rectal cancer of any stage, be disease free or have stable disease, able to speak and read English, and access to Internet and a mobile phone. Individuals with contraindications to moderate-to-vigorous physical activity (MVPA) or exercising ≥30 min ≥5 d/wk were excluded. We explored the impact of the intervention (n = 20) vs. usual care (n = 21) on MVPA via ActiGraph GT3X+ accelerometers pre-/post-intervention. Results: The intervention was feasible and acceptable. On average, participants were 54 y, BMI 28 kg/m2 and enrolled 1.5 y after diagnosis; 59% were women, 73% were White, and 61% were stage III. The intervention arm wore their Fitbits a median of 74 d (89% of study days, IQR: 23-83 d) and responded to 74% (34) of the 46 text messages that asked for a reply (IQR: 28-82%). Older participants were more likely to wear the Fitbit ( r: 0.72; p < 0.001). Married participants were more likely to wear the Fitbit and respond to texts compared to unmarried (96% vs. 32% wear time, p: 0.02 and 85% vs. 46% response rate, p: 0.006). Most patients (88%) reported that the intervention motivated them to exercise and that they were satisfied with their experience. On average, the intervention arm increased MVPA by 14 min/d, while the control arm increased by only 1 min/d, but there was no statistically significant difference in change in MVPA between groups (mean difference comparing change in MVPA in the intervention vs. control: 13 min/d; 95% CI: -14, 40; p: 0.33). Conclusions: A 12-wk physical activity intervention with a Fitbit and text messages is feasible and acceptable among CRC patients after treatment. Larger studies are needed to determine whether the intervention increases physical activity. Clinical trial information: NCT02966054.