bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant chemoradiotherapy with S-1 in patients with borderline resectable pancreatic cancer.
Authors: Hattori Masashi , Fujii Tsutomu , Suenaga Masaya , Yamada Suguru , Kanda Mitsuro , Iwata Naoki , Kobayashi Daisuke , Tanaka Chie , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Nomoto Shuji , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2017

302

Background: The aim of this study was to investigate the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) with S-1 (oral fluoropyrimidine) followed by surgery for the treatment of borderline resectable pancreatic cancer that involved the major visceral artery or the portal venous system. Methods: Twenty-eight patients with pancreatic cancers that abutted the SMA in 10, the CHA in 7, the both SMA and CHA in 1, and occluded the SMV/PV in 10 were treated with NACRT at a single institution. Radiation therapy was delivered at a total dose of 50.4 Gy in 28 fractions. S-1 was administered orally at a dose of 80 mg/m(2)/day for 14 consecutive days followed by a 7-day rest period during radiation therapy. After radiotherapy and 2 courses of S-1, restaging was done to evaluate secondary resectability. Results: Of the all patients, 25 underwent a full course of NACRT, and NACRT terminated in 3 patients because of grade 3 leukopenia in 2 and tumor bleeding in 1. Partial response was achieved in 3 patients and stable disease in 22. Twenty-four patients (86%) underwent surgical resection, and all had margin-negative (R0) resections. Only two patients (8%) had major morbidity as Clavien-Dindo’s classification III or more, and there was no operative or in-hospital mortality. Pathological examination revealed that more than 50% of tumor cells had disappeared in 14 cases and all cases achieved Evans’ score IIa and more. Conclusions: Neoadjuvant chemoradiation with S-1 was feasible and promising therapy for borderline resectable pancreatic cancer that involves the major artery or the portal venous system.
Effects of valproic acid as a histone deacetylase inhibitor in combination with S-1 on advanced pancreatobiliary tract cancers: Clinical study phases I and II.
Authors: Iwahashi Shuichi , Shimada Mitsuo , Utsunomiya Toru , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Arakawa Yusuke , Kanamoto Mami , Saito Yu
Published: February 2017

306

Background: Pancreatobiliary tract cancers are the most aggressive of human cancers. Histone deacetylase (HDAC) is well known to be associated with tumori-genesis through epigenetic regulation, and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We are conducting a clinical trial of combination therapy using valproic acid (VPA, a HDACI) and S-1, that is an oral fluoropyrimidine derivative consisting of 5-fluorouracil. Methods: Patients with advanced pancreatobiliary tract cancers were eligible for this clinical trial. The 12 patients, in whom a curative operation was not feasible, were enrolled in this study. Patients received S-1 orally at 80 mg/m2 total daily dose on days 1 to 28, followed by a 14 day recovery period. They also received VPA orally at 15 mg/m2 total daily dose, twice daily. Results: One patient had partial response (PR); ten patients were recorded as stable disease (SD); and one patient showed progressive disease (PD). Eight patients had clinically significant drug-related adverse events. The most frequent adverse events were platelet depletion and fatigue. Grade 3/4 adverse events, including anemia and platelet depletion, were observed. Significant increases in the blood concentrations of VPA were confirmed two and four weeks after VPA administration. Conclusions: This clinical study suggests that the combination therapy of VPA and S-1 for the patients with pancreatobiliary tract cancers had a manageable safety profile and preliminary antitumor activity. Clinical trial information: 000004525.
Survival trends in unresectable hepatocellular carcinoma and the effect of DEB-TACE: SEER versus tertiary cancer center.
Authors: Xing Minzhi , Prajapati Hasmukh J. , Kokabi Nima , Camacho Juan C. , El-Rayes Bassel F. , Kim Hyun Sik
Published: February 2017

308

Background: Long-term survival in patients with advanced unresectable hepatocellular carcinoma (HCC) treated with drug-eluting bead transarterial chemoembolization (DEB-TACE) vs. best supportive care has not been investigated in large-scale population studies. Methods: Under IRB approval, our institute’s cancer registry was queried for patients with advanced unresectable HCC diagnosed from Sept 2005 to Dec 2010, treated with DEB-TACE. Eighteen registries of the U.S. Surveillance, Epidemiology and End Results (SEER) database were queried for patients with advanced HCC not amenable to surgery/radiation diagnosed in the same time period. Baseline characteristics, median overall survival (OS) from HCC diagnosis and median OS from first DEB-TACE were stratified by national/state cohorts. Survival analysis and 95% confidence intervals (CI) were calculated using Kaplan-Meier estimation. Results: A total of 231 patients who underwent DEB-TACE for unresectable HCC (Group A) and 20,897 patients with unresectable HCC who received neither radiation nor cancer-directed surgery (Group B) were included. Both groups were similar for mean age at diagnosis, gender, race, bilobar disease, portal vein thrombosis and mean largest tumor size (p>0.05). Median OS from HCC diagnosis was 21.8 months (Group A; 95% CI, 18.1-25.4) and 4.0 months (Group B; 95% CI, 3.9-4.1), p<0.001. Median OS from first DEB-TACE was 15.0 months (Group A; 95% CI, 9.6-20.4). Interval survival rates from HCC diagnosis for Group A vs. B were: 99% vs. 65% (1 month), 92% vs. 49% (3 months), 75% vs. 36% (6 months), 58% vs. 35% (1 year), 36% vs. 9% (2 years), and 20% vs. 4% (3 years). Conclusions: DEB-TACE in patients with unresectable HCC demonstrated significantly greater median OS and favorable long-term survival rates compared to best supportive care in a population-based study. [Table: see text]
Relationship of ethnicity and overall survival (OS) in Asian patients (pts) on sorafenib for advanced hepatocellular carcinoma (HCC) in British Columbia, Canada.
Authors: Peixoto Renata D'Alpino , Renouf Daniel John , Gill Sharlene , Cheung Winson Y. , Kennecke Hagen F. , Lim Howard John
Published: February 2017

311

Background: Although both the SHARP and the Asian-Pacific trials showed improved OS for sorafenib when compared to placebo, the magnitude of benefit was substantially less for Asian pts, who have a higher prevalence of hepatitis B (HBV) infection. Whether the worse prognosis is related to ethnicity or to the etiology of HCC remains unclear. BC has a sizeable Asian population that can provide a good comparison to Caucasian pts with HCC. The aim of this study was to identify prognostic factors among pts with HCC who received sorafenib. Methods: 257 consecutive pts with advanced HCC who initiated sorafenib from January 2008 to February 2013 were identified using our pharmacy database. Clinicopathological variables and outcomes were retrospectively collected. Prognostic factors were assessed by univariate (Kaplan-Meier curves and log-rank tests) and multivariate analyses (Cox proportional hazards models). Results: Median age was 62 years (range 22-93), 80.5% were men, and 37.7% were Asian. Among them, 34.2% had HBV and 29.6% had hepatitis C (HCV). In addition, 68.4% had cirrhosis and 46.3% had liver-limited disease. Median progression-free survival (PFS) was 3.7 months (95% CI 3.2-4.1). Median OS from initiation of sorafenib to death was 7.4 months (95% CI 5.7-9.1). On univariate analysis, good ECOG PS, AFP < 250 and history of HCV were associated with better OS (p < 0.001, 0.002 and 0.025, respectively). Ethnicity, age, gender, HBV, cirrhosis and extra-hepatic metastases were not significantly associated with OS. On multivariate analysis, good ECOG PS, AFP < 250 and HCV positivity correlated with better OS (p < 0.001, 0.001 and 0.006, respectively), while ethnicity did not. Conclusions: When treated with sorafenib at the same institution, Asians and Caucasians with advanced HCC had similar OS. ECOG PS, AFP and HCV were the only significant prognostic factors. A higher proportion of HCVpositivity might explain why the SHARP trial achieved better OS when compared to the Asian-Pacific trial.
Fifteen-year experience of all patients (pts) with small bowel adenocarcinoma (SBA), treated in a specialized gastrointestinal (GI) oncology unit: Royal Marsden (RM) experience.
Authors: Khan Khurum Hayat , Peckitt Clare , Sclafani Francesco , Trivedi Sachin , Jain Vikram Kumar , Stanway Susannah Jane , Cunningham David , Chau Ian
Published: February 2017

316

Background: Small bowel adenocarcinoma (SBA) is a rare tumour with poor prognosis. There is paucity of published literature due to rarity of disease; we conducted this retrospective study to determine the clinical course and outcome along with prognostic factors in both early and later stage SBA. Methods: Clinical characteristics and outcomes of all pts treated consecutively in the GI Unit RM, 1996-2011 were recorded. The study endpoints were relapse free survival (RFS), progression free survival (PFS), and overall survival (OS), in early stage pts (G1) and in pts with advanced disease (presentation or relapse with un-resectable disease=G2). In G2 response rate (RR) to chemotherapy was determined. In both groups association to baseline prognostic factors were sought by performing Cox regression univariate analysis (UVA). Results: Eighty four pts with SBA were treated 1996-2011. A total of 48 presented with early stage disease (G1). In G1 (58.3% males; mean age, 57 years), 44/48 pts underwent R0 resection; 21 received adjuvant chemotherapy. RFS, PFS and OS in this group were 29.6 [95% confidence interval (CI) 3.3-55.9], 31.1 (CI=8.0-54.3) and 42.9 (CI=0-94.9) months (m), with median follow up of 76.4 m. Poor histological differentiation (p=0.025), abnormal CEA at presentation (P=0.082), and lymphovascular invasion (p=0.003) were prognostic of OS. G2 comprised of 36 pts with un-resectable disease along with 23 from G1 who subsequently relapsed [G2 (n=59); 52.5% males; mean age, 59 years]; 54 pts with metastatic and 5 with locally advanced disease; 78% received first-line chemotherapy. Overall RR of pts who received chemotherapy was 50%. OS and PFS were 12.8 (CI =8.4-17.2) and 8.8 (CI=5.5-12.3) m respectively; 1-year survival was 60.9% vs. 27.3% (no chemotherapy) (p=0.042). Abnormal albumin (0.041), platelet count (p=0.007) and CEA (p=0.025) were prognostic of OS in the chemotherapy group; doublet (18/41) versus triplet (23/41) chemotherapy were not prognostic (p=0.185). Conclusions: Pts with SBA and metastatic disease may derive benefit from systemic chemotherapy; prospective clinical trials are required to evaluate this further.
The enhanced antitumor effect of combined triptolide and paclitaxel on pancreatic cancer cell lines.
Authors: Wang Wei , Lin Wenjie , Wang Qingda , Zhuang Xin , Luo Jinbing
Published: February 2017

335

Background: Pancreatic cancer is a disease with dismal prognosis and its treatment options are limited. Recently albumin-bound paclitaxel (nab-paclitaxel) was approved by FDA for advanced pancreatic cancer patients. This study aims to explore the enhancement of therapeutic effect on human pancreatic cancer cell lines (AsPC-1 and PANC-1) via the combination of triptolide, derived from the herb Tripterygium wilfordii, and paclitaxel. Methods: Pancreatic cells were treated with paclitaxel or triptolide alone, and the combination of them. Cell proliferation was measured by sulforhodamine B (SRB). Apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-3, 8, 9 and PARP. To explore the role of nuclear factor kappaB (NF-kB) activity in pancreatic cancer cell lines, AsPC-1/IkBaM and PANC-1/IkBaM cells (NF-kB activity of cells was silenced by IkB-a mutation) were treated with triptolide plus paclitaxel and NF-kB activity were analyzed. Results: Triptolide demonstrated cytotoxicity on pancreatic cancer cell lines with the IC50 of 25-40nM. The combination of triptolide (IC30 concentration) and paclitaxel enhanced the cytotoxicity significantly . Combination index (CI) indicated that the effect of triptolide plus paclitaxel was synergistic. Furthermore, pancreatic cancer cells treated with triptolide plus paclitaxel exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with paclitaxel or gemcitabine alone. In the mechanism study, the combination of triptolide and paclitaxel did not demonstrate synergistic effect on AsPC-1/IkBaM and PANC-1/IkBaM cells. It indicated that the enhanced effect of triptolide plus paclitaxel was correlated with NF-kB activity. Conclusions: (1) the combination of triptolide and paclitaxel enhances the apoptosis in vitro, low concentration of triptolide showed synergistic effect with paclitaxel; (2) the antitumor effect of triptolide plus paclitaxel on pancreatic cancer is mediated by the induction of apoptosis and triptolide enhances paclitaxel-mediated apoptosis via suppression of NF-kB activity.
Outcomes of patients treated with capecitabine and temozolamide (CapTem) for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs.
Authors: Peixoto Renata D'Alpino , Noonan Krista , Kennecke Hagen F. , Lim Howard John
Published: February 2017

343

Background: Retrospective studies have demonstrated high response rates among patients with advanced PNETs treated with CapTem while responses are infrequently seen among non-PNETs. The objective of the study was to describe progression free survival (PFS) and overall survival (OS) among sequential NET patients treated with CapTem and to identify factors associated with response. Methods: Patients who initiated therapy with CapTem between 2009 and 2013 for advanced NETs and referred to one of 6 provincial cancer treatment centers were included. Patients received Cap 2000 mg/m2 day 1-14 and TMZ 200 mg/m2 on days 10-14 every 28 days. Their characteristics and outcomes were retrospectively analyzed. Results: In our cohort, 29 patients (16 male) with a median age of 59 (range 26 – 76) received palliative CapTem, 15 of them as first-line chemotherapy and 14 as subsequent lines. Primary tumors included pancreas (48.3%), small bowel (20.7%), lung (10.3%), unknown (10.3), rectum (6.9%) and appendix (3.4%). Median number of cycles was 3. For the entire cohort, median PFS and OS were 4.7 and 20.2 months, respectively. Although pancreatic NETs (PNETs) had shorter OS (18.8 months versus not reached, p=0.37), their PFS was longer than non-PNETs (4.9 versus 2.8 months, p=0.178). There was no difference in PFS between first or subsequent lines of therapy. Patients with Ki67 above 10% had a shorter PFS when compared to lower Ki67 (3.1 versus 5.5 months, p = 0.028). Three patients had to discontinue CapTem due to poor tolerance (2 intractable nauseas and 1 myocardial infarction). There were no treatment-related deaths. Conclusions: CapTem showed good activity among NETs, especially for PNETS, who derived the greatest benefit. Effectiveness was not exclusive to first-line therapy and seems better for well-differentiated tumors.
Living with hepatocellular carcinoma from the patient perspective: A longitudinal study.
Authors: Hansen Lissi , Vaccaro Gina M. , Rosenkranz Susan J.
Published: February 2017

373

Background: Hepatocellular carcinoma (HCC) is a growing problem. For those diagnosed with terminal HCC, there is no curative treatment. Despite a high death rate, no longitudinal studies were found examining the illness experience of patients with HCC as they are approaching death. The aim of this study was to describe the experience of living with terminal HCC and how it may affect end of life care from the perspective of patients. Methods: This was a longitudinal, prospective mixed methods pilot study using quantitative and qualitative approaches. Semi-structured interviews were conducted with a convenience sub-sample of 14 patients with HCC once a month for a 6-month period. The interview guide included questions about living with HCC, pain and symptom management strategies, treatment decisions, and any current concerns of significance. Interview data were analyzed using qualitative description. Results: This poster reports on qualitative analysis of 45 interviews from the sub-sample. Eleven patients were male and 3 were female (mean age=61.5, range=54-68 years). Findings included 4 major themes: 1) illness perceptions, 2) uncertainty about treatments over time, 3) quality of life, and 4) coping strategies. Patients perceived HCC as isolating as compared to other cancers. Patients lacked information to prepare them for the journey ahead. They struggled with symptom management over time and chose to stop treatment, delay treatment in hope of improvement, or regretted starting treatment once underway. Conclusions: For patients, the impact of HCC and treatment side effects on quality of life was challenging and filled with uncertainty. From this first step, knowledge gained is serving as the foundation for a proposed larger scale study. The goal is to develop future interventions to address challenges (e.g., symptom management and treatment decision making) at the end of life for these understudied cancer patients.
Prevalence and incidence of comorbidities associated with gastric cancer.
Authors: Danese Mark D. , Gleeson Michelle L. , Langeberg Wendy J. , Ke Juan , Kelsh Michael A.
Published: February 2017

39

Background: Understanding the burden of comorbidities in patients with gastric cancer may aid in treatment planning and evaluating the safety of new treatments. Methods: Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare combined dataset, we identified 12,612 patients diagnosed with gastric cancer 2000–2007. A cohort of 12,612 cancer-free individuals was frequency-matched by Medicare enrollment year and county of residence. Subjects were ≥66 years-old at index date to allow for ≥1 full year of Medicare coverage. Prevalence the year before index date and 3- and 12-month incidence rates (per 100 person-years) after index date were estimated for 42 common comorbidities. Results: Comorbidities with the highest (≥8%) 3-month incidence in patients with gastric cancer are shown. Conclusions: Comorbidity prevalence before index date was modestly higher, and incidence rates after index date were much higher in gastric cancer patients than in cancer-free individuals. The potential reasons for this include the increased diagnostic testing, physician visits, and reporting of morbidities that occurs with the diagnosis of cancer, as well as the effects of cancer and its treatment. [Table: see text]
Incidence of diabetes among patients with colorectal cancer.
Authors: Singh Simron , Rochon Paula , Anderson Geoffrey , Earle Craig , Fischer Hadas , Austin Peter , Yun Lingsong , Lipscombe Lorraine
Published: February 2017

393

Background: Emerging data show an increasingly recognized risk of colorectal cancer (CRC) in patients with type 2 diabetes (DM) likely due to common biologic pathways. Few data are available on DM incidence among patients with CRC. Our objective was to determine whether patients with CRC have a higher incidence of DM compared to those without CRC. Methods: We conducted a population-based retrospective cohort study in Ontario, Canada, using administrative databases comparing the incidence of DM among all CRC patients identified in the Ontario Cancer registry from Jan 1, 2002 to Dec 31, 2011 with an age-matched control population without CRC. We used Cox proportional hazard to study the association. We modeled the effect of CRC on the cause-specific hazard of developing DM and censored subjects at the time of a competing event. Subgroup analysis was performed on patients receiving chemotherapy vs. not, metastatic disease vs. not and colon vs. rectal cancer. Results: We identified 39,707 persons with CRC and 198,535 controls. The mean age was 68 and 48.6% were female. We found an overall DM incidence of 8.7% over a mean follow up time of 4.8 years. On multivariable analysis, the effect of CRC on the instantaneous hazard of the DM incidence varied over time, and thus we estimated instantaneous hazard ratios (IHR) for years 1-5 of follow up. The risk of DM among CRC patients was significantly higher than controls for at least five years post CRC diagnosis. The overall DM incidence was higher in patients with no metastasis (10.6% vs 8.6%, p<0.01), and lower in patients who received chemotherapy (8.0% vs 9.0%, p<0.01). Conclusions: This is among the first study to report an increased DM incidence among CRC survivors. This association may be due to common risk factors rather than a treatment effect, as the risk remains elevated for at least five years post diagnosis. The hazard may be underestimated, as patients with advanced cancer may not be formally diagnosed with DM. These results strengthen our understanding of the common biologic pathway of both diseases and have major implications for survivorship care in patients with CRC. [Table: see text]
Positron emission tomography/computed tomography for optimized colon cancer staging and follow-up.
Authors: Engelmann Bodil E. , Loft Annika , Kjær Andreas , Nielsen Hans J. , Berthelsen Anne Kiil , Binderup Tina , Brinch Kim , Brünner Nils , Høyer-Hansen Gunilla , Gerds Thomas A. , Kristensen Michael Holmsgaard , Kurt Engin Y. , Latocha Jan E. , Lindblom Gunnar , Sloth Carsten , Højgaard Liselotte
Published: February 2017

408

Background: Optimal management of colon cancer requires detailed assessment of extent of disease. Diagnostic accuracy of 18F-fluorodeoxyglucose (FDG) positron emission tomography/ computed tomography (PET/CT) in primary colon cancer staging and for detection of recurrence was investigated. Methods: PET/CT for preoperative staging was performed on 66 prospectively included patients with primary colon cancer. Diagnostic accuracy for PET/CT and CT alone was analysed. Forty-two stage I-III colon cancer patients had PET/CT follow-up examinations every six months for two years. Serological levels of Tissue Inhibitor of Metalloproteinases (TIMP-1), Carcinoembryonic Antigen (CEA), and liberated domain I of urokinase Plasminogen Activator Receptor [uPAR(I)] and FDG-uptake related tumour gene expression were analysed. Results: Accuracy for T-, N- and M-staging by PET/CT were 82 % [95% Confidence Interval (CI) 70; 91], 66 % [CI 51; 78] and 89 % [CI 79; 96]; for CT 77 % [CI 64; 87], 60 % [CI 46; 73] and 69 % [CI 57; 80]. Cumulative relapse incidences for stage I – III colon cancer at 6, 12, 18 and 24 months were 7.1 % [CI 0; 14.9]; 14.3 % [CI 3.7; 24.9]; 19.0 % [CI 7.1; 30.9] and 21.4 % [CI 9.0; 33.8]. PET/CT diagnosed all relapses detected during the first two postoperative years. High preoperative TIMP-1 levels were associated with significant hazards towards both risk of recurrence and shorter overall survival. FDG-uptake in colon cancer showed significant correlation to hexokinase 2, the hypoxia marker carboanhydrase IX and the proliferation marker ki67. Conclusions: This study indicates PET/CT to be a valuable tool for staging and follow-up in colon cancer. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow-up.
The cost of one added day of survival by targeted therapy in metastatic colorectal cancers.
Authors: Guirgis Helmy M.
Published: February 2017

421

Background: Data was collected to assess the cost of one day of added survival over control in metastatic cancer. Aflibercept and regorafenib have been approved as last resort treatments in refractory colorectal cancer (mCRC). Objective: Study the impact of number of cycles on overall survival gain (OSg) in refractory and first-line mCRC. Methods: Average Wholesale Prices in United States dollars (US$) of evaluated drugs and ancillary costs were added. The total was divided by reported median OSg in days. Plans were designed to rate and score drugs. Results: See Table. The data was collected to share with physicians, patients, and authorities, not for drug comparison. Conclusions: The cost of one-day survival gain by aflibercept and regorafenib was relatively high. Increased number of cycles of targeted therapy increased cost/OSg and decreased ratings and scores. [Table: see text]
Targeted analysis of progressive metabolic perturbations in colorectal cancer in colorectal adenoma: Potential for a serum metabolomics-based colorectal cancer screening test.
Authors: Farshidfar Farshad , Weljie Aalim , Kopciuk Karen A. , Vogel Hans J. , Hilsden Robert , McGregor Elizabeth , Bathe Oliver F.
Published: February 2017

426

Background: Colorectal cancer (CRC) could be resected and cured if detected at an early stage. A serum metabolomics-based screening test would represent a rapid and convenient means to identify adenoma and early CRC. However, changes in the metabolome with such minimal disease may be too subtle if the usual high throughput discovery approach were taken. We postulated that adenoma-associated metabolic changes could be better identified by targeting our analysis to metabolites that changed in a progressive manner with sequential stages of disease. Methods: Sera from patients with locoregional (LR CRC) and metastatic (mCRC) disease (stage I n=21, stage II n=30 , stage III n= 35, stage IVa n=67) and matched controls (n=121) were analyzed by gas chromatography-mass spectrometry (GC-MS). After normalization, batch correction and autoscaling, 249 features were selected. Metabolites that characterized CRC were filtered by identifying those metabolites that increased or decreased in a progressive manner with higher disease stage. Subsequently, sera from 31 adenoma patients and 31 matched controls, collected under standardized conditions prior to colonoscopy and polypectomy, were analyzed by GC-MS. "The variable importance” of metabolites identified in the first analysis were studied. Results: Products of fatty acid metabolism (dodecanoic acid, 2-amino butanoic acid, isocaproic acid, hexadecanoic acid) and urea were among metabolites that were altered more markedly in advanced disease stages. A number of metabolites that changed in this progressive fashion were found to change to a more subtle degree in adenoma. Conclusions: A targeted analysis of metabolites that change in a progressive fashion as CRC progresses represents a means to identify the subtle changes in the serum metabolome that accompany adenoma. This demonstrates the feasibility of developing a serum metabolomics-based screening test for CRC. In addition, extension of this selection approach can be used in other applications where minimal disease is challenging to detect with conventional statistical methods.
Retrospective review of FOLFIRI with or without bevacizumab (bev) for patients (pts) with metastatic colorectal cancer (mCRC): Reviewing a single-center standard clinical practice.
Authors: Maroun Jean Alfred , Marginean Horia
Published: February 2017

434

Background: Use of bev with FOLFIRI proved, in clinical trials, to be well tolerated and clinically effective in mCRC pts. In this single-center retrospective review we assess outcomes of mCRC pts on standard first-line treatment with FOLFIRI alone and FOLFIRI bev in routine care. Methods: Patients treated with FOLFIRI at TOHCC from Jan 1, 2004 to Aug 10, 2010 on a first-line mCRC were followed until August 10, 2012. According to bev availability three groups of pts can be identified: treated with FOLFIRI bev and treated with FOLFIRI alone before and after bev availability (Sept 5, 2005). Results: Of 526 pts, 470 (89%) were eligible; 176 (37%) treated with FOLFIRI with bev and 294 (63%) with FOLFIRI alone—127 (43%) before and 167 (57%) after bev availability. At the start of FOLFIRI therapy there was no significant difference among the 3 groups: median age 62 (range 36-83), 61 (32-81), 64 (28-85) years, male 54%, 72%, 64%, respectively. Pts treated with FOLFIRI bev received a median 19 cycles (range 2-78) of FOLFIRI and a median of 15 cycles (range 2-63) of bev; 89 (51%) discontinued bev before FOLFIRI. Pts treated with FOLFIRI alone received a median 12 cycles (range 3-35) before bev availability and 13 cycles (2-48) after. Toxicity was responsible for at least 1 dose adjustment in 146 (83%) pts on FOLFIRI bev and 215 (73%) pts on FOLFIRI alone. Bev was held in 95 (54%) pts; once 35%, twice 25%. The median time off bev was 37 days. Median PFS was 17 months (95%CI 13-20) for patients treated with FOLFIRI bev. When we consider patients treated with FOLFIRI before bev availability median PFS was 13 mo (95%CI 10-17) and 14 mo (95%CI 10-16) when we consider pts post bev availability. Over a period of 3 years the survival rates in three groups of pts (FOLFIRI bev, FOLFIRI alone before bev availability, FOLFIRI alone post bev availability) were 1 year 90%, 77%, and 78%; 2 years 67%, 49%, and 56%; 3 years 54% , 31%, and 44%. Conclusions: Pts treated with FOLFIRI bev received more cycles of chemotherapy however with more dose adjustments. There is a relevant benefit in terms of PFS and a more substantial advantage in terms of 1, 2 and 3 years survival rates with the addition of bev to FOLFIRI.
PET scan as a prognostic marker in advanced colorectal cancer.
Authors: Kollepara Sri Lakshmi S. , Choi Minsig , Heilbrun Lance K. , Smith Daryn W. , Shields Anthony Frank , Philip Philip Agop
Published: February 2017

442

Background: Clinical utility and ability to prognosticate using FDG-PET scan in metastatic colorectal cancer (mCRC) has not been well studied in previous literature. We hypothesized that standardized uptake value (SUV) in post treatment FDG-PET predicts clinical outcomes. Methods: We retrospectively reviewed mCRC patients who had pre and post treatment FDG - PET scans during 2005-2012 at Karmanos Cancer Institute. Primary end points of time to progression (TTP) and overall survival (OS) were compared between the two groups (follow up SUV = 0 vs. SUV > 0) using log-rank testing. Results: Study population consisted of 44 patients (median age of 58.1 years). Forty (91%) of these patients were treated first line and 34 (77 %) received an Oxaliplatin based regimen. Forty-one patients had both pre- and a post-treatment SUV. The 12 patients with post treatment SUV= 0 and the 29 patients with post-treatment SUV > 0 had median OS of 42 and 25.2 months, respectively; they had median TTP of 8.2 and 6.9 months, respectively. The patients with post treatment SUV= 0 had significantly longer OS (p = 0.0310) and weakly significantly longer TTP (p = 0.0628) compared to the patients with post-treatment SUV > 0. Conclusions: Systemic therapy decreased SUV on follow-up PET scans in the study population. Absence of FDG uptake on follow up PET scan was associated with longer OS and was suggestive of longer TTP in patients with metastatic colorectal cancer.
Predictors of radiotherapy-related gastrointestinal toxicity from anal cancer DP-IMRT: Secondary analysis of RTOG 0529.
Authors: Olsen Jeffrey R. , Moughan Jennifer , Myerson Robert J. , Abitbol Andre , Kunos Charles , Johnson Douglas , Schefter Tracey , Chen Yuhchyau , Fisher Barbara Jean , Michalski Jeff M. , Narayan Samir , Chang Albert , Crane Christopher H. , Kachnic Lisa A.
Published: February 2017

460

Background: Radiation Therapy Oncology Group (RTOG) 0529 assessed feasibility of dose-painted intensity-modulated radiation therapy (DP-IMRT) to reduce the acute morbidity of chemoradiation with 5-fluorouracil (5FU) and mitomycin-C (MMC) for T2-4N0-3M0 anal cancer. This secondary analysis was performed to identify patient (pt) and treatment factors associated with acute and late gastrointestinal (GI) adverse events (AEs). Methods: RTOG 0529 treatment plans were reviewed to extract dose-volume data for tightly contoured small bowel (SB), loosely contoured anterior pelvic contents (APC), and uninvolved portions of colon outside the clinical target volume (UC). T-tests were performed to evaluate differences in the mean absolute volumes of each critical structure receiving doses ≥ 5 to 60 Gy (V5-V60) in 5 Gy increments between pts with and without ≥ grade (G) 2, acute and late GI AEs, and ≥G3 acute GI AEs using the NCI Common Terminology Criteria, version 3. Acute is defined as ≤ 90 days from the start of treatment and late is > 90 days. Additional factors (age, location, gender, race, Zubrod, grade, size, stage, prone vs supine position) were also evaluated in multivariate (MV) logistic regression (acute AEs) or Cox proportional hazards models (late AEs) to evaluate correlation with GI AEs. Results: Among 52 evaluable pts, ≥G2 acute, ≥G2 late, and ≥G3 acute GI AEs were observed in 35, 17, and 10 pts, respectively. Trends (p<0.05) towards statistically significant associations were observed between: ≥G2 acute GI AEs and SB dose (V20-V40); ≥G2 late GI AEs and APC dose (V60); ≥G3 acute GI AEs and APC dose (V5-V25), increasing age, tumor size >4cm, and worse Zubrod. SB and APC dose parameters remained correlated with GI AEs on MV analysis. Treatment in the prone vs supine position correlated with lower SB V10-V35 and APC V5-V20, although no significant differences in GI AEs were observed. Conclusions: Acute and late GI AEs from 5FU/MMC chemoradiation using DP-IMRT correlates with RT dose to the SB and APC. Further analysis is underway to determine critical structure cut-point parameters that may aid treatment plan optimization for anal cancer DP-IMRT. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. Clinical trial information: NCT00423293.
Phospholipid ether analogs for the detection of colorectal cancers.
Authors: Deming Dustin A. , Maher Molly , Leystra Alyssa A. , Grudzinski Joe , Clipson Linda , Albrecht Dawn , Washington Mary Kay , Matkowskyj Kristina , Pazoles Christopher J. , Hall Lance T. , Lubner Sam Joseph , Weichert Jamey , Halberg Richard B.
Published: February 2017

486

Background: The treatment of pts with localized colorectal cancer (CRC) depends on the resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and regional lymph nodes is needed. Novelos, Inc. has developed a new phospholipid ether analog therapeutic and diagnostic platform. Molecules from this platform have shown to preferentially accumulate in multiple cancer types. CLR1502 is a near-infrared fluorescent labeled phospholipid ether analog, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer or a therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in human metastatic CRC. Methods: Mice with loss of APC and a constitutively active PI3K in the distal small intestine and colon develop multiple intestinal tumors ranging from benign adenomas to locally advanced adenocarcinomas. These mice were injected intravenously with CLR1502. At necropsy 96 hours after injection, the intestine was removed and tumors were analyzed using a Spectrum IVIS Caliper Life Science Imager and Fluobeam Handheld Imager. The intensity of the fluorescent signal was correlated with the histological characteristics for each individual intestinal tumor. In addition, SPECT imaging with 131I-CLR404 was performed as part of a clinical trial in patients with advanced solid tumors. Results: Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76E+10 vs 3.27E+9 respectively, p=0.027). Metastatic spread to the mesentery and mesenteric lymph nodes was detected with near-infrared fluorescent imaging. Similarly, 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Conclusions: CLR1502 and 124/131I-CLR1404 hold great promise for enhancing our ability to treat CRC. CLR1502 may enhance our ability to properly resect CRCs through better localization of the primary tumor and improve staging through the identification of involved lymph nodes. 124/131I-CLR1404 has the advantage of detecting distant disease.
Phosphodiesterase 10, a novel target in colon cancer.
Authors: Russo Suzanne , Li Nan , Lee Kevin , Xi Yaguang , Zhu Bing , Gary Bernard , Ramirez Veronica , Gurpinar Evrim , Canzeroni Joshua , Fajardo Alexandra , Sigler Sara , Piazza John T. , Chen Xi , Andrews Joel , Li Yonghe , Eberhardt Brian , Yet Larry , Keeton Adam , Grizzle William E. , Piazza Gary
Published: February 2017

503

Background: Elevation of intracellular cGMP is known to inhibit tumor proliferation and induce apoptosis, although the phosphodiesterase (PDE) isozymes that regulate cGMP levels in tumor cells have not been well studied. We report first evidence that PDE10 is elevated in colon tumors compared with normal colon and suggest that PDE10 inhibitors can be used for the treatment or prevention of colon cancer. Methods: PDE10 protein and mRNA levels were measured in human colon tumor cells (HT29, HCT116, SW480, Caco2), normal colonocytes (NCM460), human clinical samples, and ApcMin/+ mouse model. Two chemically distinct PDE10 selective inhibitors, PQ-10 and Pf-2545920, were tested against the cell lines. The NCI-60 panel of human tumor cell lines was also screened against Pf-2545920 to identify potential differences in sensitivity among histologically diverse tumor types. We also performed siRNA knockdown studies in colonocytes and tumor cell lines. To determine the effect of the PDE10 siRNA knockdown on cyclic nucleotide hydrolysis, whole cell lysates from transfected cells were assayed for PDE activity using cGMP or cAMP as substrates. Results: PDE10 levels were low in normal colonocytes (NCM460) and elevated in tumor cell lines. Similarly, PDE10 was elevated human clinical specimens and the ApcMin+/ mouse model compared with normal mucosa. PDE10 inhibitors and siRNA selectively inhibited colonic tumor growth while stable knockdown inhibited colony formation and increased doubling time. Pf-2545920 also supressed growth of all cell lines within the NCI-60 panel. In comparison with lysates from vector control cells, transfection with PDE10 siRNA reduced cGMP hydrolysis by ~35% in both HCT116 and HT29 cell lines, but did not affect cGMP hydrolysis in colonocytes; siRNA did not significantly affect cAMP degradation in all 3 cell lines. Conclusions: PDE10 plays a role in colon tumorgenesis whereby inhibitors can selectively suppress tumor cell growth. The mechanism by which PDE10 inhibition affects growth appears to involve activation of cGMP/PKG signalling. PDE10 represents a novel anticancer target for the treament and prevention of colon cancer.
Prescribing preferences (PPrefs) of U.S.-based medical oncologists (MOs) for choice of therapy after failure of first-line FOLFOX plus bevacizumab (FFB) in patients with metastatic colorectal cancer (MCC).
Authors: Bendell Johanna C. , Britton Susan L. , Lankford Maria , Buettner Arden , Green Mark R. , Neely Douglas , Scharf Mitchell
Published: February 2017

533

Background: Phase III trials have tested biologic (bio) agents (bevacizumab [bev], anti-EGFR antibodies, ziv aflibercept [ziv]) plus chemotherapy (CT) vs. CT alone after failure of first-line therapy in patients given CT + bev first line. Several have shown improvements in progression-free and overall survival (OS) with the CT + bio approach, but it is not clear how these therapies are being used in the “real life” setting. Methods: Since 3/2013 PPrefs for this setting among 276 MOs were studied using a validated, proprietary, live, case-based market research tool. A core scenario and variations based on KRAS status and first-line therapy outcome were tested (S1, S2, S3, S4). PPref data acquired using blinded audience response technology. All sources of research support were blinded. Core scenario: 49 yr old female with cecal mass, liver/lung metastases, confirmed wt KRAS for S1-3, given FFB first line. S1: FFB x 16 wks → excellent PR → 5FU bev X 16 wks → progressive disease [PD]; S2: FFB x 16 wks → excellent PR → bev alone x 16 wks → PD; S3: FFB → stable disease [SD] x 5 months as best response [BR] → PD; 4) Here changed to mutKRAS; FFB x 8 wks → PD as BR. Results: Findings shown below (Table). Conclusions: In scenarios with wt KRAS, first-line response to FFB, a majority plan bev again second line. If BR to FFB is SD in WT KRAS, anti-EGFR antibody-based therapy is used more often. In S 1-3, ziv is the PPref of 7 - 14% of MOs studied. With mutKRAS and PD as BR to FFB, use of an antiangiogenic + second-line CT is preferred by > 80%, nearly equally split between bev and ziv. Recent phase III trial data showing OS benefits are reflected in current MOs first failure PPrefs. [Table: see text]
Ziv-aflibercept in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety data from the global aflibercept safety and quality-of-life program (ASQoP and AFEQT studies) in patients ≥65.
Authors: Bordonaro Roberto , Sobrero Alberto F. , Frassineti Luca , Ciuffreda Libero , Aprile Giuseppe , Thomas Anne L. , Moore Yan , Zilocchi Chiara , Dochy Emmanuelle , Taïeb Julien , Ferry David Raymond
Published: February 2017

545

Background: The prespecified analysis of patients ≥65 years of age in the VELOUR study demonstrated a safety profile similar to that of ziv-aflibercept (Z) (known as aflibercept outside the United States) plus FOLFIRI in the overall VELOUR study. Results from VELOUR supported the initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of two clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) to capture QoL and safety data from a target population similar to that of VELOUR in a real-life setting. We report early safety data from this interim analysis for patients ≥65 y. Methods: ASQoP and AFEQT are single-arm, open-label trials evaluating safety and QoL of Z in mCRC patients previously treated with an oxaliplatin-containing regimen. Eligible patients received Z (4 mg/kg) q2wks on day 1 of each cycle followed by FOLFIRI until disease progression, unacceptable toxicity, death, or investigator/patient decision. Initial starting doses and subsequent dose modifications are at the treating physician’s discretion. The percentage of patients ≥65 y with grade (G) 3/4 adverse events (AEs) in the combined safety population of ASQoP and AFEQT are compared with that of the prespecified analysis in patients ≥65 y from VELOUR. Results: At data cut-off, the safety population comprised 116 patients with at least 1 completed cycle of treatment; 53 (45.7%) were ≥65 y. At least 1 G3/4 AE was experienced by 64.2% of patients vs 89.3% in VELOUR. Most reported G3/4 AEs were G3. There were no reports of G4 hypertension, diarrhea, stomatitis, or proteinuria. Conclusions: Thisinterim safety analysis from ASQoP and AFEQT in patients ≥65 y has identified no new safety signals. The early interim analysis provides additional safety data and suggests an acceptable toxicity profile in this real-life setting. Clinical trial information: NCT01571284. [Table: see text]
Potential predictive markers of chemotherapy for advanced gastric cancer: Biomarker study in GC0301/TOP-002, randomized phase III study of irinotecan plus S-1 versus S-1.
Authors: Sugimoto Naotoshi , Tsuburaya Akira , Kawabata Ryohei , Nishikawa Kazuhiro , Imamoto Haruhiko , Tsujinaka Toshimasa , Esaki Taito , Horita Yosuke , Kimura Yutaka , Fujiya Tsuneaki , Takayama Osamu , Oono Ryo , Yabusaki Hiroshi , Taguri Masataka , Morita Satoshi , Koizumi Wasaburo , Tan Patrick , Ninomiya Motoki , Furukawa Hiroshi , Sasako Mitsuru ,   JGCA
Published: February 2017

55

Background: Irinotecan plus S-1(IRI-S) achieved longer median survival than S-1 monotherapy and was well tolerated for patients with advanced gastric cancer (AGC) in GC0301/TOP-002, but it did not show significant superiority (Gastric Cancer 2011). According to subset analyses, IRI-S may have extra survival benefit in some group of patients, prompting to explore prognostic or predictive markers.We correlated expression of 5 genes related to DNA and anticancer drug metabolism (TS, DPD, Topo-I, ERCC1, TP) with outcome of patients in each arm. Methods: Paraffin-embedded primary tumor specimens before chemotherapy were available from 126 of 326 patients. mRNA expression in microdissected tumors was measured by real-time RT-PCR, and categorized into low and high using the median as a cut-off. Multivariate analysis for overall survival (OS) adjusting baseline factors, gene expression and treatment (S-1/IRI-S) was performed with a Cox regression model. Interaction tests were also carried out between gene expression and treatment. Results: Although baseline factors of the subjects were similar to the entire GC0301/TOP-002 trial, median survival seemed opposite; 13.1M for S-1 and 11.4M for IRI-S arm, p=0.192. 92 samples, 47 of S-1 and 50 of IRI-S arm, were assessable for 5 genes. Multivariate analyses showed that liver metastasis correlated with poor prognosis (HR, 2.73; 95% CI, 1.50-5.01; P=0.011), but no gene was significantly correlated with OS. There were interactions between the treatment effect for DPD and TP. HRs between high and low DPD were 3.02 in S-1 and 0.96 in IRI-S arm, p=0.012 for interaction; while those for TP were 2.98 in S-1 and 0.38 for IRI-S arm, p=0.002. In patients with low TS and high Topo-I (n=18), OS was 11.2M for S-1 and 18.6M for IRI-S arm, p=0.531. Conclusions: The correlative analyses suggest DPD and TP are predictive factor for the first-line treatment of AGC including S-1 and irinotecan. Combined biomarker analyses with the previous randomized phase III study including S-1 or irinotecan is warranted to verify these findings.
Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 metastatic colon cancer patients.
Authors: Hanna Nader , Woods Corinne , Zheng Zhiyuan , Onukwugha Ebere , Seal Brian S. , Mullins C. Daniel
Published: February 2017

559

Background: The purpose of this study was to investigate the association between multiple chemotherapy/biologic treatment lines and survival among patients diagnosed with metastatic colon cancer (mCC). Methods: Patients aged 66 to 105 years old diagnosed with mCC between 2003 and 2007 were selected for analysis from the Surveillance, Epidemiology and End Results SEER-Medicare data to determine the association between chemotherapy/biologic treatment lines and survival. We examined the survival benefits using Cox proportional-hazards regressions with inverse probability weighting method to adjust for the probability of receiving treatment lines. Results: Patients with no chemotherapy/biologic treatment had an adjusted median survival time of 6.8 months. Each chemotherapy/biologic treatment line received was associated with longer adjusted median survival times: 11.9 months, 23.2 months and 26.4 months for receipt of first-line treatment only, second-line treatment and subsequent treatment, respectively. Colon cancer-specific mortality hazard ratios (HRs) were 0.637, 0.391 and 0.350 (p<0.001 for each) for first-line, second-line and subsequent treatments, respectively. Overall mortality hazard ratios were 0.604, 0.398 and 0.364 (p<0.001 for each) for first-line, second-line and subsequent treatments, respectively. Compared to receiving only first-line treatment, proceeding to second-line treatment was associated with longer colon cancer-specific survival (HR=0.614, p<0.001) and longer overall survival (HR=0.659, p<0.001). Patients with a low-graded tumor had longer colon cancer-specific and overall survival (HR=0.746, p<0.001; HR=0.762, p<0.001, respectively) and lived 5.6 months longer. Factors associated with shorter survival were a higher age category and being female. Conclusions: Among mCC patients who survived at least 3 months from diagnosis, each chemotherapy/biologic treatment line was independently associated with significantly longer survival. Proceeding from first-line to second-line therapy or having a low-graded tumor was also associated with longer survival. Proceeding from second-line third-line therapy showed neither benefit nor harm.