bluuebunny/crossref_metadata_2025 huggingface dataset:
Traditional Japanese oral mucositis medicine hangeshashinto to upregulate antimicrobial peptides in human salivary gland cells.
Authors: Kono Toru , Kaneko Atsushi , Omiya Yuji , Miyano Kanako , Uezono Yasuhito
Published: February 2017

517

Background: The cause of chemotherapy-induced oral mucositis (COM) is thought to be direct injury and indirect stomatotoxic effects that result from the release of inflammatory mediators, loss of protective salivary constituents, and therapy-induced neutropenia. We previously found that gargling with hangeshashinto (HST), a traditional Japanese medicine, was effective for treatment of COM. Focusing on the pain and inflammation of COM, we reported at ASCO-GI 2013 and DDW 2013 that HST exhibited ameliorating effects in a hamster model of COM and multi-targeted effects on prostaglandin E2 (PGE2) production, followed by identification of active ingredients by PGE2 culture systems and LC-MS/MS. Our aim in this study was to address whether HST affects protective oral constituents. Methods: Human oral keratinocytes (HOK) and human salivary gland (HSG) cells were used for cell culture assays. Expression levels of mRNAs for antimicrobial peptides, extracellular matrixes, keratinocyte growth factor, amylase, COX-1/COX-2, and cNOS/iNOS in cells with or without HST (10–300 μg/mL) treatment were measured by RT-PCR. Results: HST increased gene expressions of some antimicrobial peptides (defensin β1, adrenomedullin, cathelicidin antimicrobial peptide), and amylase 1A in HSG cells. Further, HST dramatically inhibited COX-2 and iNOS mRNAs in IL-1β treated HOK cells, while it exerted no or little effect on expressions of any protective oral constituents in non-treated HOK cells. A random test to identify the ingredients that increase defensin β1 revealed that isoquinoline alkaloids like berberine were active. Conclusions: HST is expected to maintain oral homeostasis through two paths: increased production of antimicrobial peptides and decreased oral damage induced by excessive prostanoids and nitric oxide. HST thus functions as a multitarget agent, indicating that it may be beneficial in COM treatment.
Association of metformin with reduced mortality in patients with colorectal cancer: A systematic review and meta-analysis of observational studies.
Authors: Singh Preet Paul , Singh Siddharth , Gonsalves Wilson I. , Grothey Axel
Published: February 2017

522

Background: Metformin inhibits mTOR and downstream pathways involved in cell proliferation and survival by inducing AMPK activation. Although its use has been associated with decreased risk of colorectal cancer (CRC), the effect of metformin on cancer related mortality is unclear. We performed a meta-analysis of published observational studies evaluating metformin use in patients with CRC and its association with overall and CRC-specific survival. Methods: Through a systematic search of PubMed and conference presentations (cut-off: August 2013), we identified 8 observational studies (18,537 total patients with CRC; 6242 CRC patients with DM) reporting the association between metformin use and survival after diagnosis of CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, metformin use was associated with a 34% reduction in mortality in CRC patients as compared to non-use (adjusted HR, 0.66; 95% CI, 0.54-0.81), albeit with high heterogeneity (I2=66.9%). After exclusion of one study, which contributed to considerable heterogeneity, a 28% reduction in mortality was considered a more conservative, consistent effect estimate (adjusted HR, 0.72; 95% CI, 0.64-0.81), with minimal heterogeneity (I2=16.2%). On restricting analysis only to patients with DM, use of metformin (vs non-use) was associated with decreased all-cause mortality (6 studies; adjusted HR, 0.63; 95% CI, 0.49-0.81) and CRC-specific mortality (3 studies; adjusted HR, 0.66; 95% CI, 0.50-0.87). Conclusions: Based on meta-analysis of observational studies, the use of metformin in diabetic patients with CRC appears to be associated with reduced all-cause mortality and CRC-specific mortality. Further prospective investigation of metformin’s effect on outcome in CRC patients is warranted.
The relationship between tumor and host factors and survival in patients undergoing adjuvant chemotherapy for colorectal cancer.
Authors: Park James Hugh , Richards Colin H. , Mcmillan Donald C. , Horgan Paul G. , Roxburgh Campbell S. D.
Published: February 2017

525

Background: The tumor microenvironment and host inflammatory responses are important determinants of outcome in colorectal cancer (CRC), however their impact on survival in patients receiving adjuvant chemotherapy remains unclear. The aim of the present study was to examine the relationship between these factors, clinicopathological characteristics and survival in patients receiving adjuvant chemotherapy for CRC. Methods: 365 patients who had undergone CRC resection at a single institution between 1997-2008 were included; 88 patients subsequently received chemotherapy. Tumor stroma percentage (TSP) and necrosis were assessed on H and E sections and graded as low or high. Local inflammatory response was assessed using the Klintrup-Mäkinen (K-M), Galon and revised Immunoscore (CD45RO+ /CD8+, and CD3+/CD8+at the invasive margin and tumor center, respectively). Systemic inflammation was assessed using modified Glasgow Prognostic Score (mGPS). Results: Patients receiving adjuvant chemotherapy were younger with a lower ASA (both P<0.05), had advanced T- and N-stage (P<0.05 and P<0.001, respectively), poor tumor differentiation (P<0.05), venous invasion (VI) (P<0.01), margin involvement, infiltrative invasive margin (both P<0.05) and high TSP (P<0.01). In those patients who received adjuvant chemotherapy, on multivariate analysis of clinicopathological factors, VI (HR 3.00, 95%CI 1.22-7.37, P=0.017), TSP (HR 3.00, 95%CI 1.26-7.12, P=0.013), K-M score (HR 5.24, 95%CI 1.21-22.68, P=0.027) and mGPS (HR 3.10 95%CI 1.47-6.55, P=0.003) were independently associated with cancer-specific survival. When the interrelationships between factors independently associated with cancer survival were examined, VI, mGPS, K-M score and TSP were independent of each other (all P>0.05). Conclusions: Compared to standard CRC pathological staging, the present results suggest that assessment of both tumor microenvironment and host inflammatory responses may have superior prognostic value compared with TNM in patients receiving adjuvant chemotherapy.
Rectal cancer treatment without neoadjuvant chemoradiation based on preoperative magnetic resonance imaging: Determinants of surgical quality in the German OCUM study.
Authors: Kreis Martin Ernst , Strassburg Joachim , Ruppert Reinhard , Ptok Henry , Junginger Theodor , Merkel Susanne , Hermanek Paul
Published: February 2017

526

Background: Preoperative chemoradiation adds functional impairment to patients undergoing total mesorectal excision (TME). Surgical quality is of paramount importance to achieve low local recurrence rates in patients operated without preoperative chemoradiation when a negative circumferential margin was shown by preoperative magnetic resonance imaging (MRI). We aimed to determine surgical quality in a prospective multicenter cohort study (OCUM) in patients selected by MRI for surgery without neoadjuvant chemoradiation. Methods: Quality of TME was assessed in three categories for 282 patients from 12 hospitals enrolled for surgery without preoperative chemoradiation (Nagtegaal et al. 2005, Quirke and Morris 2007). Tumor perforation, local tumor cell dissemination and number of lymph nodes were assessed. Further, negative predictive value of MRI for histopathological involvement of the circumferential margin was determined. Results: In patients undergoing TME the muscularis propria plane (category III) was reached in 1/282 patients (0,4 %). Intraoperative tumor cell dissemination was observed in 3/282 patients (1,1 %). Total number of lymph nodes was 25 (median, range 10-79) and 79/282 patients had positive lymph nodes (28 %). The number of 12 lymph nodes recommended by UICC was not reached in one patient. Preoperative MRI correctly predicted a negative circumferential margin involvement as determined by histopathological workup in 98,9 % of patients. Conclusions: Excellent results in terms of surgical quality are possible justifying surgery without pretreatment in patients with MRI-negative circumferental margin tumors. This concept avoids additional functional impairment and reduced quality of life following preoperative chemoradiation in selected patients. Clinical trial information: NCT01325649.
The prognostic significance of MET overexpression in Chinese patients with gastric adenocarcinoma.
Authors: Li Jin , Wang Chenchen , Su Qin , Wang Yanong , Shi Yingqiang , Sun Menghong , Liu Lian , Sun Zuojun , Liu Xin , Li Wenhua , Zhao Xiaoying , Ji Dongmei , Peng Wei , Yu Hui , Zhang Zhe , Zhang Xiaowei , Piao Yongzhe , Hsu Wanling , Bai Sally Yan , Wang Xiyuan
Published: February 2017

53

Background: MET, receptor for hepatocyte growth factor (HGF), has been proposed as a therapeutic target in gastroesophageal cancer (GEC). The purpose of this study was to evaluate MET expression in Chinese patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma and to correlate expression with clinicopathologic parameters and prognosis. Methods: MET protein expression was assessed by immunohistochemistry (IHC) in paraffin-embedded tissues from resected tumor specimens. MET IHC was conducted using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems Inc., Tucson, AZ). Four MET IHC scores were defined: 3+ (≥50% of tumor cells staining with strong intensity); 2+ (≥50% of tumor cells with moderate or higher staining, but <50% with strong intensity); 1+ (≥50% of tumor cells with weak or higher staining, but <50% with moderate or higher intensity); or 0 (no staining, or <50% of tumor cells with any intensity) (Spigel et al, J Clin Oncol 2011;29:Suppl, Abst 7505). Kaplan-Meier was used to estimate OS and differences between MET subgroups were compared using the log-rank test. Univariate survival analysis was performed using the stratified Cox model. Results: 442 resected gastric adenocarcinoma samples were collected from patients who underwent surgery between Sept 2007 and Feb 2010. After excluding patients with missing survival, MET, tumor location, differentiation status and stage data, 362 samples were analyzed. Stage II and III accounted for 23% and 59%, respectively. MET prevalence by IHC was: 3+, 5.5%; 2+, 19.6%; 1+, 37.0%; 0, 37.9%. At the OS cut-off, 15 Apr 2012, median follow-up was 35.3 months (range 5.9–49.8 months). The group with MET IHC scores of 2+ or 3+ had significantly shorter OS compared to those with scores of 0 or 1+. The 2-year survival rate was 64% in the 2+/3+ group and 73% in the 0/1+ group (p=0.047). The HR for MET 2+/3+ versus 0/1+ was 1.65 (95% CI: 1.13–2.39, p=0.009), stratified by stage, tumor location and differentiation status. Conclusions: MET expression in resected tissue from Chinese patients with GEC was correlated with poor prognosis. This finding further supports the development of anti-MET agents in this patient population.
Randomized phase II trial of preoperative chemoradiotherapy with or without cetuximab in locally advanced rectal adenocarcinoma.
Authors: McCollum A. David , Kocs Darren M. , Chadha Punit , Monticelli Michael A. , Boyd Thomas E. , Fain Jerry Dean , Kasper Michael , Sanchez James , Simon Miklos , Singh Paramjeet , Thummala Anu , Vukelja Svetislava J. , Wang Yunfei , Asmar Lina , Richards Donald A.
Published: February 2017

537

Background: Treatment for locally advanced rectal cancer (LARC) includes preoperative radiation concurrent with fluoropyrimidine chemotherapy (CRT). Local recurrence is a problem. Cetuximab is active in colorectal cancer and is effective with radiotherapy in other diseases. This study evaluated the pathologic response rate for LARC treated with preoperative chemoradiotherapy w/wo cetuximab. Methods: LARC (T3/4 or LN+, M0) pts were randomized to Arm1/Arm2. Arm 1 received standard pelvic radiotherapy (5040-5400cGy in daily fractions) with continuous infusional 5-FU (225mg/m2/day); Arm 2 received identical chemoradiotherapy + concurrent cetuximab (400mg/m2 initial dose) 1 week before pelvic radiotherapy, followed by 250mg/m2 weekly for the duration of chemoradiotherapy. After study treatment completion, pts were re-evaluated clinically and radiographically for clinical response. After 6-8 weeks, patients underwent surgical resection. The primary end point was pathologic CR (pCR), and secondary endpoints included ORR, RFS, OS, and local recurrence rates. Results: 139 pts were enrolled (Arm 1=69/Arm2=70); Arm1/Arm2 median age 61/55 yrs, and stage II and III 59%, 39%/40%, 60%. In 124 postsurgery pts, pCR occurred in 17 Arm 1 pts (28.3%, 95% CI 17.5-41.4) and 17 Arm 2 pts (26.6%, 95% CI 16.3-39.1); TRG postsurgery was similar between treatment arms (Table). Grade 3 and 4 toxicities were largely nonhematologic: diarrhea 16%/22%, rash 0%/12%, dehydration 5%/8%, mucositis 5%/6%. The 5-yr RFS for Arm1/Arm2 was 61%/65%, 5-yr OS was 66%/83%, local recurrence was 3%/4%. Conclusions: The addition of cetuximab to preoperative CRT for LARC was associated with increased but manageable toxicities. pCR rates were similar between treatment arms, as were survival statistics and local recurrence rates. No association was found between KRAS status and pCR. Clinical trial information: NCT00527111. [Table: see text]
Observational study of the first-line chemotherapy including cetuximab in patients with metastatic colorectal cancer: CORAL trial.
Authors: Muro Kei , Itabashi Michio , Hashida Hiroki , Masuishi Toshiki , Kotake Masanori , Denda Tadamichi , Ohashi Yasuo , Sugihara Kenichi
Published: February 2017

539

Background: The combination therapy of Cetuximab (Cmab) + chemotherapy is one option as the first-line chemotherapy for KRAS wild-type metastatic colorectal cancer (mCRC). The efficacy of Cmab+FOLFIRI has been shown by CRYSTAL trail. There has been little experience of Cmab as the first-line chemotherapy in Japan, the data on Cmab combined with other drugs are insufficient, and efficacy according to the ESMO guideline groups (groups 1, 2, 3) has not yet been reported. Methods: The subjects were mCRC patients with PS 0-2 who received the first-line chemotherapy including Cmab, either in combination with chemotherapy or as monotherapy. Treatment duration, reason of discontinuation of the first-line chemotherapy (PD, conversion to surgery, adverse events), the second-line treatment, time to treatment failure, progression-free survival, response rate (RR), changes in paraneoplastic symptoms, skin symptoms (incidence, degree, prevention), and incidence and degree of other adverse events were investigated. Results: The 578 patients from the 158 institutes between January 2012 and June 2013 were enrolled. There were PS0/1/2 at 409/144/25, male/female at 368/210, median age of 65 (31-88) and groups 1/2/3 at 172/231/175. KRAS was wild type/mutant type/undetermined in 95.5%/2.4%/2.1%. Chemotherapies combined with Cmab were oxaliplatin-based/irinotecan-based/others (377/176/25). In evaluable cases, RR in groups 1/2/3 were 68.3%/50.8%/41.7%. In the frequency of skin symptoms reported up to 8 weeks/16 weeks, acneform rash was observed in 70.1%/62.1% (all grades) and in 1.2%/5.7% (grade 3 or higher), while paronychia was in 32.1%/40.6% (all grades) and in 2.6%/9.4% (grade 3 or higher). Liver resection rate and survivals are to be examined in the future. Conclusions: This is the first report on the first-line chemotherapy using Cmab, with RR as efficacy and skin symptoms as safety. Efficacy of the patients with the first-line chemotherapy using Cmab is different among 3 groups. This study is sponsored by the Public Health Research Center Foundation CSPOR in Japan. Clinical trial information: UMIN000007275.
A comparison of biologics in first-line advanced colorectal cancer: A Bayesian network meta-analysis of EGFR inhibitors and bevacizumab.
Authors: Kumachev Alexander , Yan Marie , Berry Scott R. , Ko Yoo-Joung , Riesco Martinez Maria Carmen , Shah Keya , Chan Kelvin K.
Published: February 2017

543

Background: Adding bevacizumab (B) or EGFR inhibitors (E) to chemotherapy have improved outcomes when compared to chemotherapy (chemo) alone in the first-line treatment of mCRC, however it is unclear which of these combinations is optimal. As the 2 RCTs presented to date were not powered to detect overall survival (OS) benefits and have shown conflicting OS results, a meta-analysis may be beneficial. Methods: We conducted a systematic review of RCTs comparing (1) E + chemo vs. B + chemo (2) E + chemo vs. chemo only, or (3) B + chemo vs. chemo only, using MEDLINE, Embase, Cochrane Central, and ASCO abstracts up to June 2013 with Cochrane methodology. Data on PFS and OS were extracted using the Parmar method. For RCTs involving E, only the K-ras WT data was included. The patient characteristics and outcomes of the reference arms of the RCTs were examined to assess for heterogeneity. Bayesian pairwise and network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios comparing E to B using WinBUGs. Results: Seventeen RCTs (8,048 patients) were identified; 15 of them contained extractable data for quantitative analysis. Direct pairwise meta-analyses (2 RCTs) comparing E vs. B showed that PFS HR=1.00 (95% credible regions (CR): 0.86-1.17) and OS HR=0.76 (95% CR: 0.63-0.92) in favour of E. Indirect comparisons of E vs. B (through the intermediate of chemo only: 5 RCTs comparing E + chemo vs. chemo only, 8 RCTs comparing B + chemo vs. chemo only) showed that PFS HR=1.31 (95% CR: 0.98-1.85) and OS HR=1.06 (95% CR: 0.93-1.22). Combining direct and indirect comparisons with NMA (15 RCTs) showed that the PFS HR=1.10 (95% CR: 1.00-1.21) (trend in favour of B) and OS HR=0.95 (95% CR: 0.85-1.06). Conclusions: The results of direct pairwise meta-analysis, dominated mostly by FIRE-3, suggested E improves OS without PFS benefits when compared to B. However, the results from indirect or combined NMA synthesizing all relevant data from the existing literature did not confirm those findings. The findings of FIRE-3 may be due to chance or trial specific reasons. The results of the upcoming CALGB 80405 will provide further direct evidence to help refine these estimates.
Residual rectal cancer after preoperative radiochemotherapy (ypT1-2): An indication for local excision instead of radical surgery?
Authors: Sprenger Thilo , Rothe Hilka , Conradi Lena-Christin , Homayounfar Kia , Beissbarth Tim , Ghadimi B. Michael , Liersch Torsten
Published: February 2017

546

Background: Preoperative radiochemotherapy (RCT) followed by total mesorectal excision (TME) has improved local tumor control and led to a significant tumor downstaging. For patients with pathologic complete response (ypT0) as well as residual tumor restricted only to the bowel wall (ypT1-2) local excision has increasingly been discussed to avoid significant morbidity and functional deficits associated with TME. Therefore we investigated the incidence, distribution and tumor-related localization of mesorectal lymph node (LN) metastases in TME specimens with ypT0, ypT1-2 and ypT3-4 rectal cancers, respectively. Methods: TME specimens from 81 patients with locally advanced rectal cancer treated with neoadjuvant RCT within the phase III German Rectal Cancer Trial CAO/ARO/AIO-04 were evaluated. The entire mesorectal compartment was screened microscopically after complete paraffin embedding. The number and localization of all detectable LN metastases was specified in relation to the primary tumor. Results: Whereas 50 patients (62%) had ypT3-4 carcinomas after neoadjuvant RCT 20 patients (25%) presented with residual tumor within the bowel wall (ypT1-2). 11 patients (14%) had pathologic complete response (ypT0). 28 ± 13.7 LN were detected per specimen. 25 patients (31%) had residual LN metastases after RCT. Although the incidence was higher in the ypT3-4 group (40% ypN+) still 25% of patients in the ypT1-2 group had a mean number of 2.2 residual LN metastases. 55% of these metastases were located afar from the primary lesion in the proximal mesorectum. No patient with ypT0 status had residual LN metastases. Conclusions: Even in patients with good response and tumors restricted only to the bowel wall (ypT1-2) after RCT there is a considerable risk for residual LN metastases. The majority of metastases were located clearly outside the tumor region. Local excision of residual rectal cancer would be accompanied by a higher rate of local failure and radical surgery with TME should remain the standard treatment in those patients.
A mapping algorithm of health preferences from EORTC QLQ C30 to health utility index mark 3 (HUI3) in advanced colorectal cancer.
Authors: Chan Kelvin K. , Tu Dongsheng , O'Callaghan Christopher J. , Au Heather-Jane , Leighl Natasha B. , Brundage Michael Donald , Jonker Derek J. , Karapetis Christos Stelios , Ringash Jolie , Zalcberg John Raymond , Hoch Jeffrey S. , Tebbutt Niall C. , Shapiro Jeremy , Price Timothy Jay , Pavlakis Nick , Van Hazel Guy A. , Mittmann Nicole
Published: February 2017

547

Background: The National Cancer Institute of Canada CO17 study, which showed that patients with advanced colorectal cancer had improved overall survival and derived health related quality of life benefits (measured with EORTC QLQ C30) when treated with cetuximab, collected health preferences with HUI3 prospectively. We examined the relationship between baseline health utilities and quality of life, and constructed a mapping algorithm to derive health utilities from EORTC QLQ C30. Methods: Data from 545 patients including baseline characteristics (age, gender, treatment arm, K-ras, ECOG PS, etc.), health preferences (HUI3), EORTC QLQ C30 five function scales, a two-item global health status (GHS) scale, three symptom scales, and six single items were obtained from the CO17 dataset. Correlations among HUI3 and EORTC QLQ C30 scales and baseline characteristics were examined. Multivariable linear regression model was constructed to develop a mapping algorithm to derive HUI3 from EORTC QLQ C30 scales and/or baseline characteristics. Leave-one-out cross validation (LOOCV) mean absolute error (MAE) and root mean square error (RMSE) were calculated to examine predictive ability. Results: The mean HUI3 was 0.717 (SD = 0.235). HUI3 was significantly correlated with baseline ECOG PS, number of disease sites and the presence of liver metastasis, but not with age, gender, treatment arms or K-ras. HUI3 was also significantly correlated with all EORTC QLQ C30 scales except the diarrhea scale. Multivariable regression showed that HUI3 remained significantly associated with four of the five functional scales (physical, role, cognitive and emotional), the pain scale and the GHS scale. A mapping algorithm consisting of these 6 scales resulted in a model with an adjusted R2 of 0.61, and LOOCV mean error of -0.00014, MAE of 0.11, and RMSE of 0.15. Conclusions: Health preferences as measured by HUI3 are significantly associated with HRQL as measured by EORTC QLQ C30 in patients with advanced refractory colorectal cancer. Our mapping will allow for the generation of health preference values in advanced colorectal cancer when only EORTC QLQ C30 results exist in order to conduct cost-effectiveness analysis.
Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.
Authors: Hubbard Joleen Marie , Kim George P. , Borad Mitesh J. , Qin Rui , Lensing Janet , Wright John Joseph , Erlichman Charles , Grothey Axel
Published: February 2017

551

Background: Sorafenib inhibits various pro-angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3-7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m2 d1, 5-FU infusion 2400 mg/m2d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1-37). Three pts with CRC had disease control > 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083. Clinical trial information: NCT01383343.
Multi-institutional assessment of sphincter preservation for rectal cancer.
Authors: Abdelsattar Zaid M. , Wong Sandra L. , Birkmeyer Nancy J. , Cleary Robert K. , Times Melissa L. , Figg Ryan E. , Peters Nanette , Krell Robert W. , Campbell Darrell A. , Hendren Samantha K.
Published: February 2017

566

Background: Rates of sphincter preserving surgery (SPS) have been proposed as a quality measure for rectal cancer (RC) surgery. However, administrative and registry-based SPS rates often lack critical patient and tumor characteristics, rendering it unclear if variations in SPS rates are due to unmeasured case-mix differences or selection criteria. The aim of this study was to determine whether hospitals’ SPS rates differ after accounting for clinical characteristics. Methods: As part of a RC quality project, 10 hospitals in the Michigan Surgical Quality Collaborative retrospectively collected RC-specific data from 2007-2012. We assessed for SPS predictors using multivariable regression. Patients were categorized as “definitely SPS eligible” a priori if they did not have any of the following: poor sphincter control, stoma preference, sphincter involvement, tumor <6 cm from the anal verge (an intentionally conservative cutoff) or metastatic disease. We compared hospital performance with and without these clinical data using Spearman’s correlations. Results: In total, 349 patients underwent surgery for RC in 10 hospitals (5/10 high volume and 6/10 major teaching). Of those, 74% had SPS (range by hospital 50%-91%). On multivariable analysis, only pre-op radiation, tumor location, hospital teaching status and hospital ID were independent predictors of SPS, but not age, sex, BMI, AJCC stage, ASA class, or hospital CRC surgery volume. Analyses of the “definitely eligible” patients revealed an overall SPS rate of 88% (65-100%). Hospital SPS rankings using crude versus clinically-adjusted SPS rates proved to be highly correlated (Spearman’s ρ= 0.9). Tumor locations suggest differing selection criteria for SPS in different hospitals (Table). Conclusions: Rates of SPS vary by hospital, even after correcting for clinical characteristics using detailed chart review. These data suggest missed opportunities for SPS, and refute the general hypothesis that hospital variation in SPS rates in previous studies is due to unmeasured case-mix differences. [Table: see text]
HER2 and HER3 expression in hepatic metastases of colorectal cancer: New targets for specific treatment approaches?
Authors: Conradi Lena-Christin , Styczen Hanna , Sprenger Thilo , Wolff Hendrik A. , Middel Peter , Nagelmeier Iris , Rüschoff Josef , Homayounfar Kia , Ghadimi B. Michael , Beissbarth Tim , Liersch Torsten
Published: February 2017

567

Background: Even though treatment options for coloretal cancer liver metastases have improved with the implementation of multimodal strategies and new agents, progression of distant metastases is still limiting the prognosis of affected patients. In this context we investigated the expression of HER2 and HER3 in patients with metastatic colorectal cancer and primary tumors. Methods: In this study 226 consecutive patients with hepatic metastases of colorectal cancer were included. HER2 and HER3 expression were determined in the tissue from resected metastases and—if available—in primary tumors. Immunohistochemical scoring (IHC 0 to IHC 3) and S-ISH-amplification-detection (for HER2) were used to determine the HER2 and HER3 status. Results: A positive HER2 status was found in 8.4% of all hepatic metastases; an overexpression of HER-3 in 74,8% of all cases. There was a high congruence of the expression pattern of HER2 and HER3 between hepatic metastases and available primary tumors (>90%). Conclusions: HER2 amplification and HER3 overexpression is detectable in a significant proportion of hepatic metastases of colorectal cancer. These results suggest that innovative new targeted treatment agents might be possible opportunities for the specific therapy of patients with HER2/HER3 positive metastatic colorectal cancer and should be further assessed within prospective clinical trials.
Prognostic value of the number of retrieved lymph node and lymph node ratio in locally advanced rectal cancer after preoperative radiation therapy.
Authors: Park Jin-hong , Shin Young Seob , Choi Eun Kyung , Ahn Seung Do , Yoon Sang Min , Kim Jong Hoon
Published: February 2017

582

Background: To assess the prognostic impact of total number of retrieved lymph node (TNN) and lymph node radio (LNR) in patients with locally advanced rectal cancer who received preoperative radiation therapy and surgery Methods: We retrospectively analyzed data from 677 patients with locally advanced rectal cancer who underwent preoperative radiation therapy followed by mesorectal excision at Asan Medical Center between October 1999 and May 2009. The median radiation dose was 50 Gy, and 674 patients (99%) underwent concurrent chemotherapy. All patients were divided into two groups according to the status of lymph node involvement. We assessed the influence of TNN on overall survival (OS) and disease-free survival (DFS) in the patients with node-negative disease (pN0, n = 490), and the prognostic value of LNR, estimated by dividing the number of positive nodes by the number of lymph nodes examined, in the patients with node-positive disease (pN1-2, n = 187). Results: The median follow-up period was 74 months.Patients with pN0 had median 12 lymph nodes examined (range, 0-38). Comparing with patients who had ≤ 8 TNN, patients with > 9 TNN had significantly higher 5-year OS (89% vs. 95%, p = 0.038) and DFS rates (81% vs. 90%, p = 0.013). Multivariate analysis showed that TNN more than 9 was significant prognostic factor for OS (p = 0.032) and DFS (p = 0.007). For patients with pN1-2, patients with low LNR (≤ 0.33, n = 144) showed significantly higher 5-year OS (33% vs. 73%, p < 0.001) and DFS rates (18% vs. 56%, p < 0.001) than high LNR group (> 0.33, n = 43). Also, low LNR was independent prognostic factor for OS (p = 0.001) and DFS (p < 0.001) in multivariate analysis. Conclusions: TNN for node-negative rectal cancer and LNR for node-positive rectal cancer are independent prognostic factors for survival outcome in patients with locally advanced rectal cancer after preoperative radiation therapy. These factors could be considered as useful prognostic indicators irrespective of current TNM staging system.
Comparing outcomes and toxicities from intensity-modulated radiation therapy and three-dimensional conformal radiation therapy for anal cancer: Is one really better?
Authors: Fredman Elisha T. , Kumar Aryavarta M. S. , Abdel-Wahab May
Published: February 2017

589

Background: Intensity-modulated radiation therapy (IMRT) has largely supplanted 3-dimensional conformal radiation (3D-CRT) for definitive treatment of anal cancer due to its decreased toxicity and potentially improved outcomes. Convincing data directly demonstrating its advantages, however, remain limited. We compared outcomes, acute, and post-treatment toxicity of patients with anal cancer treated with concurrent chemotherapy and IMRT vs. 3D-CRT. Methods: We performed a single institution retrospective review of patients treated with IMRT or 3D-CRT as part of definitive Mitomycin-C/5-FU based chemoradiation for anal cancer from January 2003-December 2012. Results: 61 and 104 patients received IMRT and 3D-CRT respectively. Overall, 92.7% had squamous cell carcinoma. The mean pelvic dose before boost was 48.3Gy and 44Gy for IMRT and 3D-CRT respectively. Complete response, partial response, and disease progression rates were similar (83.6%, 8.2%, 8.2% for IMRT; 85.6%, 6.7%, 7.7% for 3D-CRT; p = ns). There was no significant difference in overall survival (p = 0.971), event free survival (p = 0.900), and local or distant recurrence rates (p = 0.118, p = 0.373). IMRT caused significantly less acute grade 1-2 incontinence (p = 0.035), grade 3-4 pain (p = 0.033) and fatigue (p = 0.030). Patients receiving IMRT had significantly fewer post-treatment toxicities (p = 0.008), outperforming 3D-CRT in 7/8 toxicities reviewed. Though total length of treatment was comparable between IMRT and 3D-CRT (43.6 and 44.5 days), the IMRT group had fewer, shorter treatment breaks (p = ns). Conclusions: This report represents the largest series directly comparing concurrent chemotherapy with IMRT vs. 3D-CRT for definitive treatment of anal cancer. IMRT significantly reduced acute and post-treatment toxicities and allowed for safe and effective pelvic dose escalation.
Prognostic factor of resection of hepatic and pulmonary metastases from colorectal cancer: A multi-institutional questionaire study.
Authors: Itabashi Michio , Hirosawa Tomoichiro , Ubukata Mamiko , Ihara Takeshi , Makao Sayumi , Kaji Sanae , Bamba Yoshiko , Hashimoto Takuzou , Ogawa Shimpei , Sugihara Kenichi , Kameoka Shingo
Published: February 2017

590

Background: Resection of hepatic or pulmonary metastases (HPM) has been accepted as appropriate therapy. However whether aggressive surgery of both hepatic and pulmonary metastases from colorectal cancer (CRC) is of value has not been verified in detail. Methods: 1,179 patients undergone complete pulmonary resection were collected from 110 institutions by the 78th Congress of the Japanese Society of Cancer of the Colon and Rectum. Data on 209 of 1,179 patients who had undergone resection of HPM from CRC were included in this study. Results: (1) Outcome of surgery: In 970 patients undergoing pulmonary resection alone, 5-year relapse free survival and 5-year survival after pulmonary resection were 41.9% and 65.3%. In 209 patients undergoing hepatic and pulmonary resection, 5-year relapse free survival and 5-year survival after pulmonary resection were 33.5% (p = 0.0016) and 57.8% (p = 0.0021). The outcomes after resection were significantly better in patients with sequentially detected metastases (5-year survival of 71.6%) than in those with simultaneously detected ones (5-year survival of 41.5%) (p = 0.0016). (2) Prognostic factor:Univariate analysis revealed three variables. These were the disease free interval less than 2 years from CRC surgery to pulmonary resection (DFI) (p = 0.005), lymph node metastases of original site (p = 0.01) and extent of hepatic metastases (p = 0.01). The other factors were not statistically significant for prognosis. Multivariate analysis revealed two variables that were major prognostic factors. These were DFI (p = 0.003), and lymph node metastases of original site (p = 0.0019). Conclusions: Resection of HPM from CRC may help to prolong the survival. Independent, significant prognositic factors were lymph node metastases of original site and the DFI from CRC surgery to pulmonary resection.
Natural history of venous thromboembolism in gastrointestinal cancers.
Authors: Metcalf Robert Lewin , Hopley Nicholas , Henry Thomas , Hasan Jurjees
Published: February 2017

593

Background: Venous thromboembolism (VTE) is a leading cause of mortality in patients with cancer. Characterisation of VTE in cancer will guide prophylactic anti-coagulation of high risk populations. Methods: We performed a retrospective analysis using electronic patient records, of 910 upper GI (UGI) cancer and 1,299 colorectal cancer (CRC) patients referred to a tertiary cancer centre to identify the incidence of VTE, its relationship to chemotherapy and impact on survival. VTE risk scores were calculated using the Khorana index (Khorana AA et al. Blood 2008 May 15;111(10):4902-7). Results: VTE were identified in 88/910 (9.7%) patients with UGI cancer (oesophageal 37%, gastro-oesophageal 24%, gastric 39%), comprising 50 deep vein thromboses (DVT) and 43 pulmonary emboli (PE). 52% were stage I-III and 48% stage IV. 56% of patients received chemotherapy up to 4 weeks before VTE. Median time to VTE from cancer diagnosis was 5.3 months (range -3 to 31.2). No difference in survival was seen for patients with VTE compared to a stage matched control group without VTE (median OS 12.5 v 9.4 months, log rank p=0.2). VTE (DVT:PE, 69:49) affected 115/1299 (8.9%) patients with CRC (25% stage I-III, 75% stage IV). Median time to VTE from CRC diagnosis was 5.4 months (range -4.3 to 54.5) for stage I-III and 8.6 months (range -4.3 to 77) for stage IV CRC. Chemotherapy was received by 41% (stage I-III) and 78% (stage IV) of patients within 4 weeks before VTE. Data to perform VTE risk score were available for 72/115 CRC patients with VTE, which classified 61.1% as low-risk (stage I-III 81.2% (13/16); stage IV 55.3% (31/56)). Again, no difference in survival was seen for patients with VTE compared to a control group without VTE matched for stage and performance status (median OS for stage I-III, 40 vs. 50.3 months p=0.41; stage IV, 20.7 vs. 18.8 months, p=0.52). Conclusions: VTE affects nearly 1 in 10 patients with GI cancer receiving chemotherapy. The peak incidence is in the first 6 months following diagnosis. Most patients have DVT and 36% are asymptomatic. No adverse impact on survival was seen for patients with VTE compared to stage matched controls implying VTE is not a prognosticator of poor outcomes in gastrointestinal cancers. Mature data will be presented at the meeting.
Comparison of adding cetuximab (Cmab) or panitumumab (Pmab) to irinotecan (IRI)-based chemotherapy in salvage line against KRAS wild-type patients with metastatic colorectal cancer (mCRC): Analysis of HGCSG0901 and 1002.
Authors: Fujikawa Koshi , Yuki Satoshi , Sasaki Takahide , Takahashi Yasuo , Iwanaga Ichiro , Uebayashi Minoru , Saitoh Soh , Koike Masahiko , Nakamura Michio , Sato Yasushi , Kudo Mineo , Tateyama Miki , Kawamoto Yasuyuki , Hisai Hiroyuki , Saito Mayuko , Onodera Manabu , Takagi Tomofumi , Sakata Yuh , Komatsu Yoshito
Published: February 2017

598

Background: Cmab and Pmab have antitumor activity and acceptable safety profiles in patients (pts) with mCRC. Although IRI-based chemotherapy combined with Cmab or Pmab has demonstrated the effectiveness in salvage-line, there has been no reported trials comparing these antibodies directly. Methods: Data of 96 pts with mCRC treated by Cmab plus IRI-based chemotherapy (Cmab/IRI) from HGCSG 0901 and 27 pts treated by Pmab plus IRI-based chemotherapy (Pmab/IRI) from HGCSG1002 were retrospectively analyzed. All patients with KRAS wild type were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin and also were never administered anti-EGFR-antibodies. Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. Results: Patient characteristics were as below (Cmab/IRI vs. Pmab/IRI); male/female 58/38 vs. 16/11, median age (range) 63(38-80) vs. 64(49-81), PS 0/1/2 52/35/9 vs. 21/6/0, number of metastatic organs 1/2/3- 29/37/30 vs. 6/12/7, prior bevacizumab administration 62.5% vs. 92.6% (p = 0.002). MST was 9.9 months in the Cmab/IRI and 14.9 months in the Pmab/IRI (p = 0.196). PFS was 4.8 months in the Cmab/IRI, as compared with 5.4 months in the Pmab (p = 0.083); the corresponding RR was 25.0 % and 18.5% (p = 0.611). After adjusting other prognostic factors with Cox proportional hazard model, the administration of Cmab/Pmab made significant difference neither for OS (HR 0.908, 95% CI 0.513-1.610, p = 0.742), nor PFS (HR 0.732, 95% CI 0.447-1.199, p = 0.732). Conclusions: In this integration analysis of two studies, there were no significant difference in efficacy between Cmab and Pmab with IRI-based chemotherapy in the salvage-line treatment of pts with mCRC.
A phase I/II study of S-1 plus oxaliplatin combined with radiation (SOX/RT) for preoperative locally advanced rectal carcinoma (JACCRO CC-04: SHOGUN trial).
Authors: Watanabe Toshiaki , Matsusaka Satoshi , Ishihara Soichiro , Kondo Keisaku , Horie Hisanaga , Uehara Keisuke , Oguchi Masahiko , Murofushi Keiko , Ueno Masashi , Mizunuma Nobuyuki , Kato Daiki , Hashiguchi Yojiro , Shimbo Taiju , Okuda Junji , Nakazawa Masanori , Sunami Eiji , Kawai Kazushige , Yamashita Hideomi , Okada Tohru , Ishikawa Yuichi
Published: February 2017

602

Background: Previous western trials of preoperative chemoradiation (CRT) in patients with locally advanced rectal carcinoma (LARC) have been shown to increase the chance of sphincter preservation and local control, and has become the standard of care in western countries. In Japan, preoperative CRT has not been utilized in LARC and its value is unconfirmed. Thus, we conducted a phase I/II study of preoperative CRT with S-1, which is widely used oral fluoropyrimidine in Japan to treat gastrointestinal cancer, plus oxaliplatin in patients with LARC. Methods: Patients with histopathologically confirmed LARC (cT3-T4, any N) were eligible. A total radiation dose of 50.4 Gy was delivered in 28 fractions over 5 weeks, and S-1 was orally administered 40mg/m2 twice a day for 5 days a week at 1st, 2nd, 4th and 5th week. Oxaliplatin was administered at a dose of 40 mg/m2 (level 1), 50 mg/m2 (level 2) or 60 mg/m2(level 3) on day 1, 8, 22 and 29. Surgery was performed within 6-10 weeks after CRT. The primary endpoint of phase I part was to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of oxaliplatin. Primary endpoint of phase II was evaluated pathologic complete response (pCR) rate at RD. Results: 13 patients were enrolled in the phase I part, 2 dose-limiting toxicities (DLTs, skipping oxaliplatin due to the grade 2 neutropenia) occurred in the dose level 3, and the MTD was not reached. In phase II, 45 patients were treated at the RD of oxaliplatin (60 mg/m2) and 44 patients (97.8%) underwent surgery. A pCR was observed in 12 patients (27.3%). The relative dose intensity of radiation, S-1, oxaliplatin was 98.4%, 94.0%, and 94.3%, respectively. The incidence of grade 3-4 diarrhea and neutropenia was 8.9% and 2.2%, respectively. Postoperative complications of any grade occurred in 27.3% of patients. Conclusions: Preoperative CRT with S-1 plus oxaliplatin showed promising results in pathological responses and favorable toxicities profiles. Clinical trial information: NCT01227239.
The efficacy of first-line IRIS with or without bevacizumab in patients with metastatic colorectal cancer: Including multivariate analysis of two phase II studies.
Authors: Yuki Satoshi , Komatsu Yoshito , Fukushima Hiraku , Sasaki Takahide , Kobayashi Yoshimitsu , Harada Kazuaki , Amano Toraji , Nakamura Michio , Kudo Mineo , Tateyama Miki , Hatanaka Kazuteru , Saitoh Soh , Miyagishima Takuto , Kato Takashi , Kawamoto Yasuyuki , Takagi Tomofumi , Iwanaga Ichiro , Miyashita Kencho , Onodera Manabu , Sakata Yuh
Published: February 2017

603

Background: The safety and efficacy of first-line IRIS (S-1 in combination with irinotecan) and IRIS/Bev (IRIS in combination with bevacizumab [Bev]) have been evaluated in patients with metastatic colorectal cancer (mCRC). To date, no randomized studies comparing these regimens have been performed. This retrospective analysis compared efficacy data for the two regimens from separate phase II studies performed at Hokkaido Gastrointestinal Cancer Study Group (HGCSG). Methods: Patients with histologically confirmed unresectable metastatic or recurrent CRC and received no prior chemotherapy were enrolled. In the first trial, patients received irinotecan 100 mg/m2 on day 1,15 and oral S-1 40 mg/m2 twice daily on days 1-14 every 4 weeks (IRIS study: HGCSG0302). In the second trial, patients received the same regimen plus Bev 5 mg/kg on day 1,15 (IRIS/Bev study). Results: A total of 40 and 52 patients were enrolled the IRIS and IRIS/Bev studies, respectively. Patient characteristics were generally similar in both groups, whereas there were more cases of good performance status and less number of metastatic organ in IRIS/Bev group. The median overall survival was 39.6 months in IRIS/Bev, as compared with 23.4 months in IRIS, corresponding to a hazard ratio for death of 0.418 (p<0.001). The median progression-free survival was 17.0 months in IRIS/Bev, as compared with 8.6 months in IRIS (hazard ratio for disease progression, 0.402; p < 0.001); the corresponding response rate were 63.5 percent and 52.5 percent (p = 0.393). In a multivariate analysis of PFS and OS, IRIS/Bev was significantly associated with longer PFS and OS compared with IRIS alone. Conclusions: In this retrospective comparison of two studies, the addition of Bev to IRIS appeared to improve outcome compared with IRIS alone in the first-line treatment of patients with mCRC.
Association of bevacizumab-free interval with efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer.
Authors: Komori Azusa , Taniguchi Hiroya , Narita Yukiya , Uegaki Shiori , Nitta Sohhei , Yamaguchi Kazuhisa , Nomura Motoo , Kadowaki Shigenori , Takahari Daisuke , Ura Takashi , Andoh Masashi , Muro Kei
Published: February 2017

610

Background: Both bevacizumab (Bev) and anti-EGFR agents are sequentially used for metastatic colorectal cancer (mCRC). Some basic studies reported the interaction between Bev and anti-EGFR agents in vivo. Therefore we hypothesized the shorter Bev-free interval may lead to poor outcome of anti-EGFR therapy. The aim of this study is to examine the association of the interval between last Bev administration and initial anti-EGFR agents with efficacy of anti-EGFR therapy. Methods: We retrospectively reviewed consecutive mCRC patients who underwent combination therapy of anti-EGFR agents and irinotecan after failure of fluoropyrimidines, oxaliplatin, irinotecan, and Bev at a single institution. We divided patients in two groups (group A: the interval between Bev and anti-EGFR agents <6M, group B: ≥6M). Results: A total of 114 patients constituted the cohort of analysis. The median age was 63; 78 (68%) patients were male. Most patients (N=100, 88%) were treated with cetuximab, and 14 patients were panitumumab. Seventy-four patients were group A and 40 patients group B, respectively. There was no significant difference in patient characteristics. Response rate was 24.7% in group A, and 50.0% in group B (p=0.0072). The patients in group B have significantly longer progression free survival (4.2 vs. 6.6 M, HR 0.65, 95% CI 0.43- 0.98, p=0.042) and longer overall survival (11.6 vs. 14.3 M, HR 0.62, 95% CI 0.39- 0.97, p=0.038). Conclusions: The short interval (<6M) between last Bev and anti-EGFR agents may interfere with the efficacy of anti-EGFR therapy.