bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic effect of angiotensin-converting-enzyme inhibitors in HCC patients treated with sorafenib.
Authors: Abouelezz Khaled , Kaseb Ahmed Omar , Hassabo Hesham Mohamed , Garrett Chris R. , Vauthey Jean-Nicolas , Li Donghui , Hassan Manal
Published: February 2017

328

Background: Experimental studies indicated that angiotensin-converting-enzyme inhibitors (ACEs) or angiotensin receptor blockers (ARBs) has a role in reducing malignant changes of the liver and may significantly improve the mortality in patients with other cancers. However it is not known whether ACE and ARB inhibitors may have prognostic impact on HCC survival outcome. We aimed at evaluating the role of ACE inhibitors and ARB blockers on the prognosis of HCC patients who have been treated by Nexavar (sorafenib). Methods: Using resources of our case-control study at MD Anderson, total of 187 (males, 76.5%; females, 23.5%) pathologically confirmed HCC had been treated by sorafenib. The overall mean age (±SD) was 62.5years ± 9.6. The majority of patients were Caucasians (62.6%) who were diagnosed at TNM stage III and IV (79.2%). Total of 89 (47.6%) patients had no evidence of hepatitis C virus (HCV) or hepatitis B virus (HBV). Median survival was calculated using Kaplan Meier product-limit method and survival rates were compared using the log rank test. Cox proportional hazards model was used to estimate the univariate and multivariate Hazard Risk Ratios (HRR) and 95% Confidence Interval (CI). Results: The overall median survival of HCC patients was 19.9 months (95% CI, 16.1-23.6). Intake of ACEs or ARBs inhibitors was reported in 94 patients (50.3%). We observed significant difference in overall median survival (months) between patients who had ACE/ARB inhibitors versus those who did not, median survival (95% CI) were 21.5 (17.1-25.8) and 14.6 (12.4-16.7), respectively, p=0.04. After adjustment for HCC prognostic factors and demographic factors, we observed 30% reduction in HCC mortality among those who received ACEs/ARBs inhibitors, the estimated HR was 0.7 (95% CI, 0.4-1), p=0.05. Conclusions: Our results may indicate that HCC patients under anti-angiogenic therapy (sorafenib) and have been under anti-hypertensive therapy like ACE/ARB may assist in depleting the collagen and may improve host matrix and tumor microenvironment to enhance drug delivery. Future analysis in a larger sample is warranted
Association of the establishment of multidisciplinary (MDC) hepatocellular carcinoma (HCC) clinic with clinical outcome.
Authors: Yopp Adam C. , Ostapoff Katherine T , Singal Amit G , Mansour John C. , Balch Glen C. , Marrero Jorge A. , Schwarz Roderich
Published: February 2017

332

Background: Multidisciplinary clinics are prevalent in the management of cancer. However, there is a lack of data demonstrating improved outcomes. The variability of liver- and tumor-specific factors in HCC mandates multimodal therapy. The aim of this study was to evaluate the impact of establishing a MDC HCC clinic. Methods: A MDC HCC clinic consisting of surgeons, hepatologists, oncologists, and radiologists was established October 2010. After this date, any patient with HCC or suspected HCC (any liver mass on radiology or elevated AFP) was evaluated in the MDC clinic. We conducted a retrospective review of a prospective HCC database to identify patients diagnosed in the year following and three years prior to initiation of the MDC clinic. Demographics, tumor characteristics, treatment regimens, and survival were compared between the two groups of patients with one-way ANOVA and Chi-squared tests. Survival curves were generated using Kaplan-Meier with log rank test. Results: 105 patients were identified in the year prior to the MDC clinic and 209 patients in the 3 previous years. There was no difference in gender, race/ethnicity, etiology of cirrhosis, or Child-Pugh stage between the groups. Patients diagnosed after the MDC clinic were found at earlier tumor stages by AJCC and BCLC classification (p=0.001 and p=0.003, respectively). More post-clinic patients received treatment (56% vs. 44%, p=0.04), and time-to-treatment was shorter (2.2 vs. 4.6 months, p=0.001) than those diagnosed prior to the MDC clinic. Median survival of patients diagnosed after the MDC clinic was significantly longer than those seen during the 3 prior years (15.2 vs. 4.7 months, p=0.002). This difference in survival persisted when patients who were lost to follow-up or died within one month of HCC diagnosis were excluded (17.7 vs. 7.0 months, p=0.004). Survival after excluding BCLC D patients was also longer in the post-clinic period (one year survival, 64% vs. 47%, p=0.001). Conclusions: Formation of a MDC HCC clinic is associated with improved survival, most likely due to more streamlined care resulting in HCC diagnosis at earlier tumor stage and shorter time to treatment.
Temporal trends in colorectal cancer screening (CRCS).
Authors: Das Siddhartha , Chen Leo , Cheung Winson Y.
Published: February 2017

356

Background: The rate of CRCS continues to be suboptimal. Our study objectives were to characterize temporal trends in CRCS in general and within specific subpopulations and identify clinical and system factors that pose barriers to CRCS. Methods: Data from respondents aged ≥50 years who were classified as average risk (no personal or family history of colorectal cancer) from the 2001 to 2009 California Health Interview Survey were analyzed. Up-to-date CRCS was defined as having had a sigmoidoscopy or colonoscopy within the past 10 years. Using multivariate regression analyses that adjusted for confounders, rates of CRCS over consecutive periods of 2 calendar years were determined. Stratified analyses that explored for effect modification based on gender, ethnicity, smoking history, educational attainment, income level, health insurance status, and urban vs. rural residence were conducted. Results: A total of 126,873 screening-eligible respondents was included: median age was 63 years (range 50-85); 50,303 (46%) were men, and 95,534 (63%) were white. In the entire cohort, only 73,589 (55%) reported up-to-date CRCS. Over time, there was a significant trend towards increased CRCS, ranging from 48% in 2001 to 61% in 2009 (p<0.01). After adjusting for confounding variables, this trend persisted with higher odds of up-to-date CRCS in more recent years (see Table). Specific characteristics were associated with decreased likelihood of CRCS: women (OR 0.63), low education (OR 0.72), poor income (OR 0.84), no insurance (OR 0.44), and rural residence (OR 0.93) (p<0.01 for all). Temporal increases in CRCS were most prominent in particular groups, such as women (OR 3.55 in 2009 vs. 2001) and the uninsured (OR 11.48 in 2009 vs. 2001) (p<0.01 for both). Conclusions: Although CRCS improved over time, there is still room for significant improvement. Temporal increases in CRCS were most substantial among women and the uninsured. Interventions used to improve CRCS in these groups should be harnessed and implemented within other minorities to enhance screening. [Table: see text]
Value of cardiophrenic angle lymph nodes for the diagnosis of colorectal peritoneal carcinomatosis.
Authors: Caramella Caroline , Malka David , Pottier Edwige , Goéré Diane , Boige Valerie , Honoré Charles , Ducreux Michel , Borget Isabelle , Dromain Clarisse , Elias Dominique
Published: February 2017

372

Background: The radiological diagnosis of peritoneal carcinomatosis (PC) is challenging. Metastases in the cardiophrenic angle lymph nodes (CPALN) have been anecdotally reported in patients with abdominopelvic malignancies. We aimed to assess whether CPALN detected by computed tomography (CT)-scan are associated with PC in patients with colorectal cancer (CRC). Methods: Between 2007 and 2010, 550 patients with CRC, including 165 (30%) with PC, underwent surgery with complete exploration of the peritoneal cavity in our center. We retrospectively reviewed preoperative CT-scans for the presence of CPALN, and assessed the association of CPALN with surgically confirmed PC by univariate and multivariate analyses. Results: CPALN were present in 123 (75%) of the 165 patients with PC, but absent in 263 (68%) of the 385 patients without PC (sensitivity (Se), 0.72; specificity (Sp), 0.68; positive predictive value (PPV), 0.49; negative PV (NPV), 0.85; odds ratio [OR], 3.3; p<0.001). The presence of CPALN was not correlated with the extent of PC, the primary tumor and lymph node status , or the presence, number, size and location of liver metastases. Among the 165 patients with PC, 99 (60%) had visible signs of PC (other than CPALN) on CT-scan; among the remaining 66 patients, CPALN were the only potential sign of CP in 41 (62%), leading to Se, Sp, PPV, and NPV in patients with no signs of CP (other than CPALN) on CT of 0.62, 0.68, 0.24, and 0.92, respectively. Conclusions: The detection of CPALN on CT may be of valuable help for the diagnosis of PC in patients with CRC.
Pharmacogenetic biomarkers for predisposition to toxicity to adjuvant FOLFOX/XELOX in colorectal cancer.
Authors: Garcia Alfonso Pilar , Muñoz Andres J. , Blanco Codeisido Montse , Lopez-Trabada Ataz Daniel , Cortejoso-Fernandez Lucia , Garcia-Garcia Maria-Isabel , Gonzalez-Haba Eva , Sanjurjo-Saez Maria , Martin Miguel , Lopez-Fernandez Luis A.
Published: February 2017

390

Background: 5-fluorouracil and capecitabine are the gold standards in colorectal cancer (CRC) treatment and are often combined with oxaliplatin (FOLFOX and XELOX chemotherapy, respectively). Our purpose was to analyze associations between severe adverse reactions to these regimes and polymorphisms in genes related to these drugs Methods: Retrospective study with 47 adult CRC patients treated with adjuvant FOLFOX/XELOX. 20 polymorphisms in 14 genes were selected: 6 genes [XRCC1 (rs25487), ERCC2 (rs131181), ERCC1 (rs11615), GSTP1 (rs1695), EGFR (rs4559542) and GSTT1 (copy number variation)] related to the pharmacokinetics and dynamics of oxaliplatin and 8 related to fluoropyrimidines [MTHFR (rs1801131 and rs1801133), DPYD (rs2297595 and rs3918290), TYMS (rs34743033 and rs34489327), ABCB1 (rs1128503, rs2032582 and rs1045642), ABCC4 (rs4148551 and rs3742106), ABCC5 (rs3805114), CYP2A6 (rs3742106 ) and CDA (rs2072671)]. Linear by linear association chi-square test (SPSS v.18.0.) was used to study associations. A multivariate analysis including sex and performance status was also conducted. p< 0.05 was considered significant. Results: Mean age was 62 (SD: 12) years and 78.7% male. Univariate analysis: statistically significant associations were obtained between rs11615 (ERCC1), neutropenia and hand-foot syndrome; rs3742106 (CYP2A6) and neutropenia; rs34743033 and rs34489327 (TYMS) and nausea/vomiting; and CNV of GSTT1 and neutropenia. Multivariate analysis: statistically significant associations were obtained between rs3742106 (CYP2A6) and neutropenia (GT vs. TT: OR, 0.042, 95% CI, 0004-0499, p = 0.012); rs2297595 (DPYD) and nausea/vomiting (GA vs AA: OR, 0.051, 95% CI, 0003-0772, p = 0.032); and rs11615 (ERCC1) and neutropenia (CC vs CT / TT: OR, 0.099, 95% CI, 0016-0615, p = 0.013) Conclusions: These results could help oncologists reduce adverse reactions associated to FOLFOX and XELOX chemotherapy by giving patients the best possible option, thus, improving their quality of life. Bigger cohorts are needed to verify the polymorphisms in ERCC1, CYP2A6, TYMS, DPYD and GSTT1 prior application in clinical practice.
Gender specific profiling in SCN1A polymorphisms and time to recurrence in patients with stage II/III colorectal cancer.
Authors: Benhaim Leonor , Gerger Armin , Bohanes Pierre Oliver , Paez David , Wakatsuki Takeru , Yang Dongyun , Labonte Melissa Janae , Zhang Wu , Ning Yan , Loupakis Fotios , El-Khoueiry Rita , Laurent-Puig Pierre , Lenz Heinz-Josef
Published: February 2017

393

Background: Voltage-gated Na + channels (VGSCs) are involved in cells signalling and strongly contribute in the process of tumour progression. Two single nucleotide polymorphisms (SNPs) in the SCN1A gene encoding the α-subunit of VGSC recently showed an interesting gender-related association with survival in patients with metastatic colorectal cancer (CRC). The current study was designed to confirm the association between SCN1A and time to recurrence (TTR) in patients with stage II and III CRC and determine the influence of the gender on this association. Methods: The study enrolled patients with histologically confirmed CRC high risk stage II and stage III treated from 1987 to 2007 with adjuvant 5-FU-based chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or in the Los Angeles County/USC Medical Center (LAC/USCMC). Peripheral blood samples were collected for each patient at the date of diagnosis. Genotypes were determined after DNA extraction and PCR amplification by direct sequencing. Results: A total of 127 males and 107 females were enrolled in this study. Baseline demographic and clinical characteristics according to the gender were similar. In univariate analysis female patients carrying the SCN1A rs3812718 TT genotype showed a significant shortened time to recurrence rate when compared to females with the alternate CT or CC genotype (HR: 2.26 [95%CI: 0.89, 5.70], p=0.039). This association remained significant in multivariate analysis. By contrast, in the male population, the shortened time to recurrence rate was oppositely associated with the CC genotype (HR: 0.49 [95%CI: 0.18, 1.38], p=0.048). For the SCN1A rs229877, in both female and male populations the CT genotype was associated with a trend for a shorter TTR. Conclusions: Our findings confirm that genomic SCN1A rs3812718 polymorphism is associated with TTR in patients with stage II and III CRC, supporting the hypothesis that this association is gender dependent. We furthermore verified the trend of a shorter recurrence rate for patients harboring the CT genotype in SCN1A rs229877 regardless of their gender.
Use of selective inhibition of nuclear export (SINE) using a CRM1/XPO1 antagonist to overcome resistance to CPT-11 in colon cancer in preclinical models.
Authors: Chung Hye Won , Salas Fragomeni Roberto A. , Shacham Sharon , Kauffman Michael , Cusack James C.
Published: February 2017

396

Background: Overcoming the resistance of topoisomerase I (TOP1) inhibitors has great clinical potential for treatment of advanced colon cancer. Previously, we showed a kind of novel CRM1-dependent SINEs leads to increase the anti-cancer effects of topoisomerase-1 (topo-1) inhibitor, CPT-11 (SN38), in colon cancer in vitro. However, its underlying mechanisms have not been fully understood. Here, we showed CRM1-dependent SINEs induced the sequestration of TOP1 into nucleus as well as other tumor suppressors or growth regulatory proteins. Methods: The synergism of KPT-251, a novel CRM1-dependent SINE, with SN38 were evaluated using Chou-Talalay method in both CPT-11/SN38-sensitive (SW480) and CPT-11/SN38-resistant colon cancers cells (WiDr) in vitro and animal experiments bearing CPT-sensitive and CPT-resistant cells in vivo. The expression change of TOP1, p-FOXO3a, p27, p53, p21, and IkBa in nucleus were evaluated by western blot. Nuclear trafficking of TOP1 was confirmed by immunofluorescence microscopy and measuring nuclear TOP1 catalytic activity. Increased apoptosis through TOP1 nuclear sequestration were evaluated by comet assay. Results: We found the dramatic synergism of KPT-251 with CPT-11 in both CPT-11/SN38-sensitive and CPT-11/SN38-resistant colon cancers cells in vitro and in vivo. We also found TOP1 was sequestrated into nucleus by KPT-251 through CRM1 inhibition, and this induced overcoming the resistance of CPT-11 in colon cancers, which were demonstrated by western blot, immunofluorescence microscopy, TOP1 catalytic activity, and comet assays. Conclusions: Our results suggest blocking TOP1 nuclear export by a novel CRM1-dependent SINE sensitizes colon cancer to TOP1 inhibitors. Our study supports the development of a novel treatment strategy to overcome the resistance of CPT-11 and other TOP1 inhibitors in colon and potentially other cancers.
Influence of KRAS mutation on recurrence patterns in patients undergoing hepatic resection of colorectal metastases.
Authors: Kemeny Nancy E. , Chou Joanne F. , Capanu Marinela , Gewirtz Alexandra N. , Cercek Andrea , Kingham T. Peter , Jarnagin William R. , Fong Yuman , DeMatteo Ronald P. , Allen Peter J. , Shia Jinru , Ang Celina , Vakiani Efsevia , D'Angelica Michael Ian
Published: February 2017

398

Background: There have been conflicting results about whether KRAS mutation influences outcome in patients (pts) with colorectal cancer. In pts who underwent liver resection, Karagkounis reported a worse recurrence and survival in KRAS mutated (MUT) patients (ASCO 2012, abs 3616). Methods: In 105 pts who underwent liver resection and received adjuvant (adj) hepatic arterial infusion and systemic chemotherapy and in whom KRAS data was available, we evaluated recurrence patterns and survival. Correlation between KRAS and clinical factors such as prior chemotherapy, post operative CEA, clinical risk score, and stage at diagnosis was evaluated using Fisher’s exact test and the Wilcoxon rank sum test. Kaplan-Meier methods were used to estimate median overall recurrence free survival (RFS) and overall survival (OS) at 4 years. Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adj therapy to bone, brain, lung and liver metastases separately. Results: Of 105 patients, 76 were KRAS wildtype (WT), and 29 were KRAS MUT (26-G12 and 3-G13). The median RFS was 26 months for KRAS WT pts and 15 months for KRAS MUT pts (p=0.08). OS at 4 years was 88% [95% CI: 78%-94%] for KRAS WT and 78% [95% CI: 57%-90%] for KRAS MUT pts (p= 0.15). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in the Table. The cumulative incidence of bone and brain metastases at 2 years was 0% and 0% in KRAS WT pts versus 16.4% [95% CI: 1.1%-31.7%] and 4.7% [95% CI: 0%-14.1%] in KRAS MUT pts (Table). There was no association between clinical factors and KRAS status. Conclusions: KRAS MUT pts appeared to have worse OS and RFS, although we were unable to show a significant difference between KRAS WT and MUT for OS and RFS. In addition, cumulative incidence of bone and brain metastases at 2 years appeared to be higher for KRAS MUT pts as compared to WT pts. Results are based on small sample size and further investigation is needed. [Table: see text]
A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with unresectable metastatic colorectal carcinoma.
Authors: Chatterjee Aradeep , Bhattacharya Sudin , Chatterjee Ashim Kumar , Chakraborty Amitava , Biswas Jaydip
Published: February 2017

407

Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating unresectable metastatic colorectal carcinoma (UMCRC). Methods: Our study was phase-II, open level, single arm and single stage. Participants eligibility criteria included (1) histopathology confirmation of the malignancy (2) metastatic and unresectable disease status (3) no prior conventional cancer treatments (4) Karnofsky performance status between 40–70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti-cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml/kg body weight/day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 105 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 12 (11.43%) cases and partial response occurred in 38 (36.19%) cases. 76 (72.38%) of them survived at least 1 yr, 58 (55.24%) survived at least 2 yrs, 51 (48.57%) survived at least 3 yrs, 43 (40.95%) survived at least 4 yrs and 37 (35.24%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with UMCRC. The investigational drug psorinum is non-toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating unresectable metastatic colorectal carcinoma to integrate it into the mainstream of oncology treatments.
Clinical significance of tumor budding in colorectal cancer.
Authors: Lee Jae-Im , An Chang Hyeok , Kim Hyung Jin , Lee Sang Chul , Oh Seong-Taek
Published: February 2017

422

Background: Tumor budding was defined as an isolated single cancer cell or a small cluster of cancer cells at the invasive margins. We assessed the clinical significance of tumor budding, as a predictor of outcomes in patients with non-metastatic colorectal cancer. Methods: We studied a total of 148 patients with colorectal cancer who underwent curative resection. Tumor budding was assessed on slides stained with hematoxylin and eosin (H&E). Tissue specimens including the entire invasive margin from largest cut sections of the whole tumor were examined. Tumor budding was not classified according to previously described classification. The actual number of tumor budding along the entire invasive margin was counted at a magnification of x200 with the use of light microscopy. We determined cut-off point of tumor budding, lymph node ratio and carcinoembryonic antigen (CEA) with receiver operating characteristic (ROC) curve. Results: Univariate analysis revealed that poorly differentiation (p=0.009), lymphatic invasion (p=0.035) venous invasion (p=0.007), CEA >6.3 (p=0.0007) and tumor budding >13 (p=0.0006) were significantly related to poor survival. Cumulative five survival rates differed significantly between patients with tumor budding ≤13 (92.3%) and those with tumor budding >13 (73.1 %). Multivariate analysis with Cox’s regression analysis demonstrated that tumor budding >13 (hazard ratio=4.925, p=0.003), poorly differentiation (hazard ratio=3.696, p=0.01) and CEA >6.3 (hazard ratio=3.085, p=0.024) were independent prognostic factors for overall survival. CEA >6.3 (hazard ratio=2.361, p=0.034) and tumor budding >20 (hazard ratio=3.293, p=0.008) were significant prognostic predictors for disease free survival Conclusions: Tumor budding is useful for prognosis and identifying patients with colorectal cancer who have a high-risk of disease recurrence after curative surgery. The proper cut-off level of tumor budding is 13.
Investigating parent of origin effects (POE) and anticipation in Irish Lynch syndrome kindreds.
Authors: Farrell Michael P. , Hughes David J. , Schmid Jasmin , Boonstra Philip S. , Mukherjee Bhramar , Walshe Margaret B. , Mac Mathuna Padraic M. , Gallagher David J.
Published: February 2017

431

Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome. We sought evidence for a specific POE effect and anticipation in Irish Lynch syndrome families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) from two hospital-based registries of MMR mutation carriers. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed using the bivariate Huang and Vieland model. Results: Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Veiland and Huang bivariate model (p < 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Genetic anticipation was present in this cohort of LS families, emphasizing the importance of early-onset screening. An additional 60 LS kindreds are under review and updated data will be presented at the meeting. [Table: see text]
Association of time to adjuvant chemotherapy (TTAC) and overall survival among patients with rectal cancer treated with preoperative radiation.
Authors: Gresham Gillian , Speers Caroline , Woods Ryan , Cheung Winson Y. , Schaff Kimberly , Fung Mayo , Kennecke Hagen F.
Published: February 2017

461

Background: Studies suggest that delayed adjuvant chemotherapy (AC) beyond 8 weeks is associated with inferior survival in early-stage colon cancer (CA). The optimal TTAC in rectal CA remains unclear. The objective of this study was to determine the prognostic effect of TTAC in stage II and III rectal CA treated with standard preoperative (op) chemoradiation. Methods: Patients with stage II/III rectal CA treated with pre-op chemoradiation, received post-op AC, and referred to the British Columbia Cancer Agency between 1999 and 2008 were included. Univariate and multivariate analyses were conducted using Kaplan Meier and Cox regression methods to evaluate the association between TTAC and outcomes. X-tiles cut-point analysis was performed to determine the optimal TTAC. Results: A total of 327 eligible patients were identified: median age 61 (range 22-85), 70% male, and 75% stage III. In terms post-op AC, 51% received 5-fluorouracil (5-FU), 32% received capecitabine, 12% received 5-FU and oxaliplatin, and 5% received other chemotherapy. Median TTAC was 7.0 weeks (wks) (range 1.6-33.3 wks). Cut-point analysis revealed the optimal TTAC to be 5.6 wks (HR: 0.42, 95%CI 0.22-0.82, p=0.0087). Initiation of AC within optimal TTAC (5.6 wks) and 6 wks from date of surgery (sx) was associated with a significant survival benefit while no significant effect was seen at 8 wks. TTAC of ≤ 6 wkswas found to be a significant prognostic factor in multivariate analysis (p=0.047) adjusted for ECOG, age, sex, stage, margin status, and grade. In stratified analysis by stage, patients with stage III disease benefited from AC (p=0.018) while those with stage II did not (p=0.71). Conclusions: In this study, the optimal TTAC was 6 weeks or less. Initiation of AC within this time frame was associated with improved OS. This is less than the optimal timeframe indicated in the literature for colon CA. [Table: see text]
Predictors of gastrointestinal toxicity during pelvic radiotherapy.
Authors: Yang T. Jonathan , Oh Jung Hun , Son Christina , Apte Aditya , Deasy Joseph O. , Wu Abraham Jing-Ching , Goodman Karyn A.
Published: February 2017

472

Background: To identify clinical and dosimetric factors associated with acute gastrointestinal (GI) toxicities due to pelvic radiotherapy (PRT) in patients with rectal cancer. Methods: We analyzed 177 consecutive rectal cancer patients treated between 2007-2010. Clinical information including age, gender, stage, chemotherapy, and weekly proctitis and diarrhea grade (CTCAE 3.0) during PRT were obtained. The bowel, rectum, and anal canal were contoured on CT treatment planning images. Doses to GI structures were calculated using the original treatment plan, and dose-volume parameters were extracted for modeling using CERR software. Logistic regression models were used to test the association between GI toxicity grade and predictors. Results: The mean age was 59; 76 (43%) patients were women; 166 (94%) received concurrent 5-FU based chemotherapy. Over half (56%) were treated with intensity modulated radiotherapy (IMRT), 44% were treated with 3D conformal RT (3DCRT). Grade 2+ proctitis and diarrhea were seen in 57 (32%) and 44 (25%) patients, respectively. On univariate analysis, age inversely predicts for Grade 2+ proctitis (Rs=-0.22, p=0.009). 3DCRT (Rs=0.27, p=0.001) and female gender (Rs=0.28, p=0.0008) predict for Grade 2+ diarrhea. On multivariate analysis, the normal tissue complication model including volume of anal canal receiving >15Gy, anal canal minimal dose, and age was most predictive of Grade 2+ proctitis (AUC=0.67, Rs=0.25, p<0.001). The model including bowel volume receiving 45Gy, female gender, and use of 3DCRT was highly predictive of Grade 2+ diarrhea (AUC=0.76, Rs=0.35, p<0.001). Patients treated with IMRT had significantly less bowel volume receiving ≥ 45Gy compared to 3DCRT (V45Gy=10.9% vs. 21.7%, p<0.0001). Conclusions: In this analysis of a large cohort of patients receiving PRT for rectal cancer, we identified clinical and dosimetric predictors of acute GI toxicity. Younger patients and women have higher rates of acute Grade 2+ proctitis and diarrhea, respectively. IMRT resulted in a 50% relative reduction in bowel volume receiving 45Gy and a lower risk for clinically significant diarrhea. Dose-volume constraints using these parameters should be considered, particularly in higher risk patients.
Patterns of care of locoregional radiation therapy in patients with stage IV rectal cancer: A SEER analysis.
Authors: Logan Jennifer K. , DiPetrillo Thomas A. , Leonard Kara Lynne
Published: February 2017

477

Background: Per the 2012 NCCN guidelines, pelvic radiation therapy (RT) is one of the preferred treatment regimens for patients with metastatic rectal cancer (MRC). This study aims to analyze patterns of care and outcomes data for the use of neoadjuvant/adjuvant pelvic RT in patients with MRC using the SEER database. Methods: Patients with stage IV rectal or rectosigmoid cancer were identified in the SEER database (1973-2009). Patients were stratified according to their primary site of disease (rectum vs. rectosigmoid), T-, and N-stage. Treatment regimens (+/- surgical resection, +/-RT, or a combination of both) were recorded. Fischer's exact test was used to compare RT rates based on stratified factors. 2-yr survival rates were compared among treatment groups. Results: A total of 6,873 patients with stage IV rectal CA and 3,417 patients with rectosigmoid CA were identified. In total, 20.5% of rectal CA patients received surgery alone while 38.7% received RT alone or RT + surgery. Within the rectosigmoid group, 51.4% of patients received surgery alone and 15.1% of patients received either RT alone or RT + surgery. The use of RT differed significantly between those with Tis-2 and T3-4 disease (p < 0.001) and between those with N0 vs. N1-2 disease (p < 0.001). 2-yr and 5-yr survival differed significantly between treatment groups with the highest survival rates among those receiving surgery and RT. Detailed data is provided in the table below. Conclusions: The primary treatments for patients with MRC include surgery +/- RT. RT is used more commonly in patient with primary rectal (as opposed to rectosigmoid) tumors, N0, or Tis-T2 disease. Treatment with combination surgery and RT is associated with prolonged survival. [Table: see text]
Effectiveness of bevacizumab (BV) beyond disease progression in metastatic colorectal cancer (mCRC): Analyses by sex in the ARIES observational cohort study (OCS).
Authors: Cohn Allen Lee , Hurwitz Herbert , Bekaii-Saab Tanios S. , Bendell Johanna C. , Kozloff Mark , Tezcan Haluk , Flick Elizabeth Dawn , Mun Yong , Fish Susan , Dalal Darshan , Grothey Axel
Published: February 2017

514

Background: Randomized trials and OCSs have demonstrated that BV treatment in 1st-line (1L), in 2L, and across multiple lines is associated with longer survival in patients (pts) with mCRC. This analysis was aimed at comparing the effectiveness of BV after 1st disease progression (PD) between male and female mCRC pts who received 1L BV-containing therapy in a real-world setting. Methods: ARIES is a large, prospective OCS that enrolled pts who received BV and chemotherapy (CT) for 1L mCRC. Post-PD effectiveness was assessed for men and women characterizing BV use by cumulative and dichotomous approaches. The primary analysis treated BV exposure as cumulative BV doses after 1st PD and post-progression overall survival (ppOS) as the time from 1st PD to death. A time-dependent Cox regression model was fitted to assess the effect of cumulative BV exposure on ppOS, while controlling for potential confounders. A dichotomous secondary analysis characterized BV exposure as receipt of CT + BV (BBP) or CT alone (No BBP) within 2 months after PD and ppOS as time from 1st PD + 2 months to death. Results: Among the 1,550 1L mCRC pts enrolled, 1,199 (532 women) had PD. In the primary analysis, hazard ratios (HRs) for ppOS decreased, on average, by 1.2% with each additional BV dose. When stratified by sex, the average risk reduction per BV dose over 15 doses was 1.8% in women and 0.7% in men. In the secondary analysis that included 331 women (BBP, 180; No BBP, 151) and 417 men (BBP, 245, No BBP, 172) who received BV ± CT within 2 months post-PD, the HRs for ppOS with BBP treatment were 0.46 (95% CI, 0.35–0.59) in women and 0.52 (95% CI, 0.41–0.67) in men. Statistical interaction tests for differences in the effectiveness of BV between men and women were negative for primary and secondary analyses (P of 0.58 and 0.77). Protocol-specified adverse events occurred in 17.8% of women and 10.2% of men in the BBP population; this difference was largely related to rates of hypertension (8.3% vs 2.4%, respectively). Conclusions: In ARIES, the effectiveness of BV after first PD was not statistically different between women and men with mCRC. Clinical trial information: NCT00388206.
The outcome of preoperative chemotherapy followed by surgery and upfront surgery for liver metastases from colorectal cancer.
Authors: Kim Jung Sun , Kim Sunyoung , Cho Hye Jeong , Shim Eun Kyung , Oh Jae Hwan , Kim Dae Yong , Han Sung-Sik , Kim Seoung Hoon , Park Sang Jae , Baek Ji Yeon
Published: February 2017

516

Background: Hepatic metastasectomy is the only curative option for patients (pts) with colorectal liver metastases (CRLM) but the optimal sequence of surgery and chemotherapy has not been established. We evaluated disease-free survival (DFS) in pts who were treated with difference sequences for resectable CRLM. Methods: Pts who had radiologically diagnosed with CRLM and underwent preoperative chemotherapy (preopCT) followed by surgery or upfront hepatic resection from Jan 2008 to Dec 2010, in National Cancer Center, Korea, were identified and their medical records were reviewed. Pts with number of metastatic nodules (mets) less than 6, and who were untreated for metastastic setting were analyzed. Those with tumor invasion of major intrahepatic vessels, extrahepatic metastases, or combined other advanced cancer were excluded. Results: Of 208 pts who underwent hepatic metastasectomy for suspicious CRLM, 123 pts who fulfilled the above criteria were analyzed. 34 (28%) pts received preopCT followed by surgery and 89 (72%) pts underwent upfront surgery. Postoperative chemotherapy was administered for 34 (100%) of preopCT group and 73 (82%) of upfront surgery group. Number of mets, baseline tumor marker levels, and R0 resection rate were similar between the two groups. But, early relapse was more in upfront surgery group. DFS at 3 year was 14% (95% CI 29%-34%) in preopCT group and 48% (95% CI 36%-59%) in upfront surgery group. In multivariate analysis, age > 65, Charlson comorbidity index > 0, mets≥3, and R1/R2 resection were significantly associated with increased risk for DFS events, while PreopCT was marginally associated with adverse outcome (Table). Conclusions: Upfront surgery, rather than preoperative chemotherapy followed by surgery, might be a favorable treatment option for resectable CRLM in terms of DFS. [Table: see text]
Treatment patterns and costs in second-line (2L) metastatic colorectal cancer (mCRC).
Authors: Teitelbaum April H. , Evans Dana , Yu Elaine , Morlock Robert , Byfield Stacey DaCosta
Published: February 2017

544

Background: Administrative claims databases are an important data source to examine treatment (tx) patterns, costs and outcomes, but are subject to limitations. This study included a chart review to assess a claims-based algorithm for identifying 2L mCRC patients (pts). Tx patterns and costs were compared between mCRC pts treated with bevacizumab (BEV) or cetuximab (CET). Methods: 2LmCRC pts were identified from a US commercial insurance claims database (1/2008-6/2011). Initial identification required pts to have ≥2 claims ≥30 d apart for colon or rectal cancer and metastatic (met) disease. Continuous enrollment for ≥6 mo before and after the date of 1st met claim, ≥2 lines of therapy (LOT), and 2L tx with BEV or anti-EGFR was required. 2L was defined as addition of any new agent ≥28 d after start of 1st LOT. Charts from 92 pts were abstracted and used to refine and corroborate the algorithm. Generalized Linear Models (GLM) were used to assess differences in healthcare costs between patients on BEV or CET during 2L. Results: The match rate of claims identified mCRC pts treated with multiple lines of therapy confirmed by chart abstraction ranged from 85% to 97%. Applying the final algorithm to the overall claims data resulted in the identification of 569 pts: 450 pts receiving BEV and 119 pts receiving CET. A total of 38 panitumumab patients were excluded from analysis due to small sample size. Pt characteristics were similar; mean age was 61 years and 58% were males. In 2L, BEV was commonly used with 5FU or capecitabine-based regimens (81%) and CET with irinotecan-based regimens (73%). BEV pts had significantly lower all-cause healthcare costs (adjusted difference: –$12,239, p=0.02), and medical costs (–$13,672, p=0.01) during 2L. While on second-line therapy, BEV pts also had lower average monthly all-cause and medical costs than CET pts. Sensitivity analysis using variations of the case finding algorithm yield similar results. Conclusions: The use of BEV during second line treatment of mCRC was found to be associated with significantly lower healthcare costs relative to the use of CET from a large US healthcare claims database.
Effect of coinfusion of dexamethasone to oxaliplatin on hypersensitivity reactions induced by oxaliplatin in patients with colorectal cancer treated with XELOX.
Authors: Aisu Naoya , Yoshida Yoichiro , Miyake Toru , Tanimura Syu , Hoshino Seiichiro , Yamashita Yuichi
Published: February 2017

560

Background: Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. The incidence of severe anaphylactic reaction of oxaliplatin is estimated to be 0.5%, whereas the incidence of other hypersensitivity reactions in clinical practice is estimated to be 12% to 20%. We have reported that there is possibility that hypersensitivity reactions to oxaliplatin could have been prevented by co-infusion of dexamethasone (DEX) (Yoshida et al.2012 ASCO-GI, Yoshida et al, Br J Med Med Res 2012) but just in a small cohort. This study was undertaken to evaluate the effectiveness of co-infusion of DEX to oxaliplatin for controlling hypersensitivity reactions caused by the administration of oxaliplatin. Methods: A retrospective study of patients with advanced colorectal cancer who received XELOX was performed. The study included 101 patients who received XELOX or XELOX +bevacizumab therapy for advanced or recurrent colorectal cancer. In all the patients, oxaliplatin (130mg/m²) was administered in combination with DEX (6.6mg) via the peripheral vein. Results: A total of 101 patients were studied. Hypersensitivity reactions developed in 2 patients (1.98%).Respiratory symptoms, ocular symptoms and anaphylaxis were not observed in 101 patients. Two patients experienced cutaneous reaction (erythema). Grade 3 or higher hemotoxicity was noted in 13.9% of the patients, and grade 3 or higher nonhematological toxicity was noted in 17.8% of the patients. The response rate was 55.4%. Conclusions: Co-infusion of dexamethasone to oxaliplatin reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive XELOX, allowing treatment to be completed as planned. We have already started a new phase II trial to confirm the effects of DEX to prevent the hypersensitivity.
A retrospective cohort study to determine the prognostic factors in metastatic colorectal cancer (mCRC) patients (pts) undergoing lung metastatectomy.
Authors: Socola Francisco , Nguyen Dao M. , Ochoa Roberto Enrique , Rocha Lima Caio Max S. , Hosein Peter Joel
Published: February 2017

565

Background: Resection of liver metastases is now accepted as a potentially curative strategy in some pts with mCRC. Resection of lung metastases (LMs) may also be beneficial but this is not well established. We hypothesized that resection of LMs may lead to prolonged survival in highly selected pts with mCRC. Methods: In this IRB-approved retrospective cohort study, cases were defined as mCRC pts with LMs as their only site of disease who underwent metastatectomy. Controls consisted of mCRC pts who had LMs but did not undergo resection. Charts were reviewed for clinical characteristics; survival data was obtained from the institutional tumor registry. The primary endpoint was overall survival (OS) in the cases versus controls. The secondary endpoint was to determine prognostic factors associated with better survival. Results: We included 26 consecutive cases of mCRC undergoing resection of LMs and randomly selected 26 controls. All pts in the both groups were treated with contemporary chemotherapy, as well as bevacizumab and anti-EGFR monoclonals when appropriate. The median OS from the time of diagnosis with LMs was 29.8 months (95% CI 22.9-36.6) in the control group versus 56.6 months (95% CI 47.3-65.8) for the cases who underwent resection (log rank p=0.04). A number of baseline factors were significantly different between the cases and controls. The control group contained more pts with poorly differentiated tumors (p=0.016); had more pts with synchronous versus metachronous presentation of LM's (p=0.001); had more pts with multiple vs solitary LM's (p<0.001); and had more pts with bilateral vs unilateral LMs (p<0.001). The interval from initial diagnosis to the onset of LMs was significantly longer in the resection group vs controls (22.9 vs 2.9 months, p<0.001). Conclusions: In this retrospective study, pts with mCRC to the lung who were referred for resection were more likely to have well differentiated, solitary, unilateral tumors, with a long interval between the original diagnosis and the onset of LMs. Pts selected using these criteria may have a significant survival benefit from surgical resection of their LMs.
A novel preoperative protocol for locally advanced rectal cancer: Hyperfractionated short-course radiotherapy combined with chemotherapy.
Authors: Doi Hiroshi , Beppu Naohito , Takada Yasuhiro , Niwa Yasue , Fujiwara Masayuki , Kimura Fumihiko , Yanagi Hidenori , Yamanaka Naoki , Kamikonya Norihiko , Hirota Shozo
Published: February 2017

577

Background: Neoadjuvant chemoradiotherapy (NACRT) has become a widely accepted strategy for rectal cancer (RC). The purpose of this study is to examine the safety and efficacy of a novel protocol of neoadjuvant hyperfractionated short-course radiotherapy (NAHSRT) combined with chemotherapy for locally advanced RC. Methods: 82 patients (pts) with RC were treated with NACRT followed by radical surgery between March 2008 and May 2012. 50 pts with RC of cT3N1M0 were analyzed in the present study. NAHSRT was performed with a dose of 2.5 Gy twice daily, with an interval of at least 6 hours between fractions, up to a total dose of 25 Gy (25 Gy in 10 fractions for 5 days) with chemotherapy. Radical surgery was performed within 3 week following the end of the NAHSRT. Results: 50 pts included 37 men and 13 women. The median age was 65.0 (range: 39-85) years. The median follow-up term was 12.0 (2-36) months. S-1, oxaliplatin with capecitabine, and fluorouracil, leucovorin plus irinotecan (FOLFIRI) was administered with NAHSRT in 48 pts, 1 pt, and 1 pt, respectively. 48 pts (96%) had no apparent adverse events before surgery. 49 pts (98%) completed NACRT except for 1 pt stopped chemotherapy (S-1) because of grade 3 gastrointestinal toxicity (CTCAE v.3). In addition, no pts showed grade 4 toxicities. Postoperative complications were found in 30 pts (60.0%). 33 pts (66.0%) received adjuvant chemotherapy. S-1, capecitabine, oxaliplatin with capecitabine, uracil/tegafur (UFT) and oral leucovorin, and oxaliplatin combined with S-1 (SOX) was delivered after surgery in 20 pts, 4 pts, 4 pts, 4 pts, and 1 pt, respectively. No pts. developed local failure, although distant failures were found in 3 pts. The median disease free survival and overall survival was 11.6 (2-36) months and 12.0 (2-36) months, respectively. In addition, disease-specific survival rate was 100.0%. Conclusions: We presented a novel protocol of NAHSRT for locally advanced RC and the short-term outcome. NAHSRT was well tolerated and produced excellent short-term outcomes in pts with locally advanced RC.
Expression of mRNA as a prognostic factor of colon-rectal cancer.
Authors: Watanabe Takafumi , Tamura Kazuhiko , Enomoto Masanobu , Saitho Hitoshi , Ohsaka Yoshiaki , Takagi Yuu , Tsuchida Akihiko
Published: February 2017

585

Background: Several cancer-associated genes are known as prognostic factors of colon-rectal cancer. We measured and compared mRNA expression levels for each gene in colon-rectal cancer tissues obtained from biopsied and excised specimens. Methods: 53 cases of colon-rectal cancer surgery were examined. By the DNP method, mRNA expression levels of cancer-associated genes were measured. Measurements and examinations were performed for 10 genes: TS, DPD, TP, FPGS, GGH, DHFR, ERCC1, Topo-I, EGFR and VEGF. Results: Among 53 patients who underwent operations for colon-rectal cancer, a comparison was conducted between 43 recurrence-free patients and 10 metastatic recurrent patients. Conclusions: The results thereof showed a tendency in metastatic recurrent cases toward decreased activity of Topo-I. Topo-I’s decrease in activity is said to be related to CPT-11 tolerance, and its low degree of activity in metastatic recurrent cases is predicted to be a factor in poor prognoses. At the same time, ERCC1 showed a tendency toward high activity in metastatic recurrent cases. ERCC1 is said to reduce sensitivity to platinum-based medications. Based on these results, further observation of the progress of treatment in each case is intended.