bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-130, a unique antibody-drug conjugate (ADC) of SN-38 targeting CEACAM5 antigen: Preclinical basis for clinical activity in metastatic colorectal cancer (mCRC).
Authors: Govindan Serengulam V. , Cardillo Thomas M. , Rossi Edmund A. , McBride William J. , Sharkey Robert M. , Goldenberg David M.
Published: February 2017

625

Background: IMMU-130 is a CEACAM5-targeted ADC, labetuzumab-SN-38, with the drug being the active form of the topoisomerase I inhibitor, CPT-11, and substituted at 7-8 moles/mole of IgG. This agent is in phase I/II clinical trials in patients with relapsed mCRC (NCT01270698; NCT01605318). Methods: Therapy experiments were conducted in female athymic nude mice (n=5-10 per group), 4-6 weeks of age, bearing s.c. LS174T human colon carcinoma xenografts of ~0.2 cm3 size, or 2 weeks after lung metastases were generated by i.v. injection of GW-39 human colon carcinoma cells. Untreated controls, including a non-targeting ADC, were included. Biodistribution was examined in the s.c model using a single 12.5-mg/kg dose of the ADC or unconjugated labetuzumab, each spiked with 111In-labeled substrate. Tolerability studies were conducted in white New Zealand rabbits. Results: In the metastatic model, fractionated dosing of a total of 50 mg/kg of ADC showed that 2 × the schedules of twice-weekly × 2 weeks with 1 week off and once-weekly × 2 weeks with 1 week off doubled the median survival vs. untreated mice, and were better than a 25-mg/kg dose given on days 1 and 15 (p < 0.0474; log-rank). Pre-dosing with as much as twice the dose of labetuzumab as the ADC dose in the metastatic model did not affect median survival (p > 0.15). Therapy experiments in the s.c. model revealed that IMMU-130, with 50% of drug released in ~20 h, was superior to the conjugate with an ultrastable linker, that the ADC was better than an MTD of 5FU/leucovorin chemotherapy (p < 0.0001), and that the ADC could be combined with bevacizumab for improved efficacy (p < 0.031). Significantly better efficacy for the specific ADC vs. nonspecific ADC was observed. Pharmacokinetics in mice indicated ~25% longer half-life for the unconjugated MAb vs. ADC, but with minimal impact on tumor uptake. A tolerability study in rabbits showed the NOAEL to be the human equivalent dose of 40-60 mg/kg, given as two doses. Conclusions: Preclinical data show an excellent therapeutic window for IMMU-130, which appears to be translated into the clinical experience thus far. The potential for combination therapy is also indicated.
The chemokines CXCL9 and CXCL13 as prognostic markers for metastasis and survival in rectal cancer patients after neoadjuvant chemoradiation.
Authors: Sprenger Thilo , Behnes Carl Ludwig , Conradi Lena-Christin , Kauffels Anne , Wolff Hendrik A. , Ghadimi Michael , Liersch Torsten , Wirtz Ralph M
Published: February 2017

627

Background: Distant metastasis is a challenging problem in multimodal treatment of rectal cancer. Valid prognostic markers for the occurrence of metachronous metastasis could help to stratify patients who qualify for adjuvant chemotherapy and intensified follow-up procedures after preoperative chemoradiotherapy (CRT). Methods: We analysed 9 different genes known to prominently figure in crucial pathways of the tumor cell metabolism. mRNA was isolated and quantified from surgical specimens of 77 rectal cancer patients undergoing neoadjuvant CRT. The panel contains genes with relevant function in apoptosis (Birc5, XIAP, SMAC) and epithelial-mesenchymal transitions (SNAI2) as well as the cancer stem-cell marker CD133, the transcription factor ESR1 and the lymphocyte-chemokines CXCL9 and 13. The expression levels in post-CRT rectal cancers were correlated with the development of distant metastasis and with disease-free (DFS) and cancer-specific overall survival (CSS). Results: Intratumoral mRNA expression of the T-cell chemokine CXCL9 (p<0.001) and the B-cell chemokine CXCL13 (p<0.01) was inversely correlated with the occurrence of distant metastasis. Patients with isolated high CXCL9 (p<0.0001) and CXCL13 levels (p<0.01) had a significantly prolonged DFS. Patients with simultaneous expression of CXCL9 and 13 had an excellent DFS compared to patients without expression of any of the chemokines (p<0.0001). Additionally, CXCL9 expression was correlated with an improved CSS (p<0.05). There was no significant correlation between expression levels of the other genes tested and metastasis or survival. Conclusions: The post-CRT expression of the lymphocyte-chemokines CXCL9 and 13 is associated with reduced rates of distant metastases and improved survival in rectal cancers after CRT. Further investigations are needed to prospectively validate these results and characterize the underlying cellular and molecular mechanisms.
KRAS mutation in colorectal cancer and its association with a stromal-derived gene signature.
Authors: Pelossof Raphael , Elkabets Moshe , Chow Oliver S , Fairchild Lauren , Chen Chin-Tung , Setty Manu , Smith Jesse Joshua , Dow Lukas E. , O'Rourke Kevin P. , Lowe Scott W. , Leslie Christina S , Garcia-Aguilar Julio
Published: February 2017

628

Background: KRAS mutation in colorectal cancer (CRC) is characterized by an altered transcriptional profile when compared to wild-type KRAS tumors. The list of differentially expressed genes overlaps significantly with a stromal fibroblast activation (SFA) signature present across multiple carcinomas. We have reported low expression of SFA genes in KRAS mutant CRC compared to KRAS wild type tumors. Here we sought to confirm the variation of the SFA signature with KRAS mutation and infer its origin in the stromal component of the tumor using experimental models. Methods: The SFA signature was assessed in an inducible-KRAS murine CRC model using RNA-sequencing, and in a CRC cell line with and without a transduced KRAS mutant vector by microarray analysis. Finally, RNA-sequencing of CRC patient-derived xenografts (PDXs) was used to determine whether the SFA signature was being expressed in the tumor epithelium or the surrounding stroma by leveraging the ability to align sequenced reads to the mouse and human genomes separately. Results: The SFA signature was identified in the inducible-KRAS mouse model, matching human cohort observations of decreased SFA gene expression in KRAS mutant CRC. On the other hand, KRAS transduction did not recapitulate the SFA signature in a CRC cell line, suggesting that the presence of stroma may be required for the expression of the SFA signature. Finally, RNA-seq reads for SFA signature genes in CRC PDXs immediately after implantation aligned primarily to the human genome but in later passages of the same PDXs aligned only to the mouse genome. These data suggest that the SFA transcriptional program is associated with the stroma rather than the epithelial tumor cells. Conclusions: KRAS mutation in CRC is associated with a gene expression signature derived from the tumor stroma. These findings suggest that KRAS mutation in the epithelial tumor cells may impact the tumor microenvironment in CRC.
A phase I/II study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer.
Authors: Yong Wei-Peng , Katsuda Masahiro , Kono Koji , Yamaue Hiroki , Rha Sun Young
Published: February 2017

65

Background: The aim of this study was to evaluate the safety and optimal dosing schedule of a HLA-restricted cancer vaccine cocktail, OTSGC-A24 targeting novel specific tumor antigens FOXM1, DEPDC1, KIF20A, URLC10 and VEGFR1 in advanced gastric cancer patients with HLA-2402 haplotype. Methods: The vaccine was administered subcutaneously at 3-weekly, 2-weekly and weekly interval. In the first phase, 3 evaluable patients were treated in each dose cohort. The decision to expand the 2-weekly and weekly cohort to 10 patients per cohort was based on specific cytotoxic T-lymphocyte (CTL) induction rate using ELISPOT assay 4 weeks after vaccination. Results: The vaccine was well tolerated at all dose cohorts. The most common toxicity seen was skin induration at the injection sites. No DLT was observed. One patient developed G2 interstitial pneumonitis, 6 months after initiation of treatment. Stable disease was seen in 4 of 9 evaluable patients. The specific CTL induction can be observed at 4 weeks post vaccination with the highest (>2 of 3) observed in the weekly and 2-weekly cohorts. One of 3 patients in the 3-weekly cohort achieved specific CTL response at 4 weeks post vaccination, although all patients attained specific CTL response by 12 weeks after vaccination. Conclusions: OTSGC-A24 combined peptide vaccine was well tolerated. At 4 weeks post vaccination, the CTL induction rate is superior in the weekly and 2-weekly cohort. Efficacy data of the expanded cohorts will be presented. Clinical trial information: NCT01227772.
Quantitative gene expression underlying 18f-fluorodeoxyglucose uptake in colon cancer.
Authors: Engelmann Bodil E. , Binderup Tina , Kjær Andreas , Loft Annika , Gerds Thomas A. , Berthelsen Anne Kiil , Brinch Kim , Latocha Jan E. , Sloth Carsten , Højgaard Liselotte
Published: February 2017

653

Background: Positron emission tomography (PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples from primary CC and surrounding normal mucosa were obtained from 42 patients. FDG uptake was quantified using maximal standardized uptake value (SUVmax). The expression of ki67, glucose transporter 1 (GLUT-1), hexokinase 1 (HK1), hexokinase 2 (HK2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF1α) and carbonic anhydrase IX (CaIX) mRNA was examined by quantitative real time reverse transcriptase-polymerase chain reaction. Results: All primary tumours showed increased uptake of FDG. The mean SUVmax was 15.0 (range 5.3 – 37.8). No correlation was found between tumour size and SUVmax. Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUVmax with gene expression levels showed significant correlations between SUVmax and HK2, ki67 and CaIX, respectively. Conclusions: These results confirm FDG PET/CT as a functional imaging method in CC, and that FDG accumulation reflects molecular events related to glycolysis, cell proliferation, hypoxia, but not angiogenesis.
A randomized, double-blind, phase II study of first-line FOLFOX plus bevacizumab with onartuzumab versus placebo in patients with metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Hochster Howard S. , Hart Lowell L. , Firdaus Irfan , Mace Joseph Ronald , McFarlane Joshua Jemison , Kozloff Mark , Catenacci Daniel Virgil Thomas , Hsu Jessie J. , Hack Stephen Paul , Shames David S. , Phan See-Chun , Cohn Allen Lee
Published: February 2017

663

Background: In mCRC, MET overexpression has been associated with poor prognosis and resistance to anti-VEGF therapy. We initiated a phase II study to evaluate the combination of onartuzumab (O), a ligand-blocking monoclonal antibody directed against the MET receptor, plus bevacizumab and FOLFOX, in first-line mCRC (GO27827; NCT01418222). Methods: This double-blind, randomized, multicenter phase II study randomized patients 1:1 to receive O (10 mg/kg iv) or placebo (P), plus mFOLFOX6 and bevacizumab (5 mg/kg iv). Stratification was by prior adjuvant therapy. All treatments were given on day 1–3 of a 2-week cycle. Oxaliplatin was given for up to 8–12 cycles; all other agents were continued until progression, unacceptable toxicity or death. Primary endpoint was progression-free survival (PFS) in ITT and MET+ subgroup by immunohistochemistry (IHC). MET status was determined by central laboratory IHC evaluation, with scores of 2+ or 3+ considered MET+. Results: From September 2011 to November 2012, 194 patients were enrolled. A recommendation was made to stop O after an interim efficacy and safety analysis in September 2013, due to lack of efficacy. The final analysis (cut-off Feb 2014) found that O did not improve PFS vs. P in the ITT (HR 0.75 [0.52–1.08]; p=0.12) or MET IHC+ populations (n=79; HR 1.03 [0.56–1.89]; p=0.93), although improvement was noted in the MET IHC− population (n=108; HR 0.60 [0.37–0.97]; p=0.03). Neither overall survival (OS) nor response rate (RR) was improved with O vs. P in any of the groups (OS HR 0.96 [0.61–1.50], p=0.85 for ITT; OS HR 1.24 [0.63–2.43], p=0.54 for MET IHC+; OS HR 0.83 [0.44–1.56], p=0.56 for MET IHC−; RR 57.3% vs. 57.7% for ITT, 43.2% vs. 57.1% for MET IHC+, 66.1% vs. 60.8% for MET IHC−). More edema (65.7% vs. 12.9%) and venous thromboembolic events (30.3% vs. 16.1%) were seen with O vs. P, respectively. Grade ≥3 events were similar (86.9% vs. 84.9%) and events leading to discontinuation were increased (48.5% vs. 37.6%) with O vs. P. Conclusions: Adding onartuzumab to FOLFOX/bevacizumab did not prolong PFS in first-line unselected or MET IHC+ mCRC. A trend towards PFS benefit was seen in those with MET IHC− mCRC, contrary to prior reports in other tumor types. Clinical trial information: NCT01418222.
GAIN-(C): Efficacy and safety analysis of imgatuzumab (GA201), a novel dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with FOLFIRI compared to cetuximab plus FOLFIRI in second-line KRAS exon 2 wild type (e2WT) or with FOLFIRI alone in mutated (e2MT) metastatic colorectal cancer (mCRC).
Authors: Bridgewater John A. , Cervantes Andres , Markman Ben , Siena Salvatore , Cubillo Antonio , Carbonero Rocio Garcia , Sigal Darren , Aprile Giuseppe , Cunningham David , Nadal Cristina , Pericay Carles , Samuel Leslie M. , Hochhauser Daniel , Perez-Fidalgo Jose Alejandro , Strickland Andrew , Guizani Cecile , Golding Sophie , Lopez Valverde Vanesa , Ott Marion Gabriele , Tabernero Josep
Published: February 2017

669

Background: Imgatuzumab, a humanized engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, showed promising clinical activity in a phase I trial including KRAS MT mCRC. This multicenter phase II study (NCT01326000) aimed to compare the combination of imgatuzumab with FOLFIRI to cetuximab plus FOLFIRI or FOLFIRI alone as second-line treatment in patients with both KRAS e2WT or e2MT mCRC. Methods: Patients underwent a mandatory fresh tumor biopsy at screening to assess KRAS exon 2 status. KRAS e2WT patients were randomized (1:1) to treatment groups 1 or 2 to receive imgatuzumab (1,400 mg IV on day 1 and 8 then q2-weekly) or cetuximab (400 mg/m2 IV on day 1 followed by 250 mg/m2 IV q-weekly) respectively plus FOLFIRI (standard IV chemotherapy). KRAS e2MT patients were randomized to groups 3 and 4 to receive imgatuzumab plus FOLFIRI or FOLFIRI alone respectively. Patients were stratified by EGFR expression, time to disease progression on first line treatment and prior treatment with bevacizumab. A run-in phase (n=6/group) was performed to confirm tolerability before recruitment proceeded. Results: 169 patients with an evaluable fresh tumor biopsy were randomized. Median PFS (Investigator reported) was 7.3 months in group 1 versus 6.1 in group 2 (HR, 1.13; 95% CI 0.69-1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57-1.54). Adverse events of ≥ grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively). Conclusions: The outcome was negative with respect to the primary efficacy endpoint (PFS) with no benefit seen for the addition of imgatuzumab to FOLFIRI in second-line in both KRAS e2WT and e2MT populations. We demonstrated that collection of fresh tumor biopsy is feasible in pretreated CRC. Clinical trial information: NCT01326000.
Raltitrexed in the management of metastatic colorectal cancer: The COMET study.
Authors: Desramé Jérôme , Dourthe Louis-Marie , Debourdeau Philippe , Mille Dominique , Artru Pascal , Albrand Helene
Published: February 2017

677

Background: Raltitrexed, indicated for palliative treatment of advanced colorectal cancer (CRC), may be useful for patients (pts) with cardiovascular (CV) risk factors, or cardiotoxicity/disease progression with prior chemotherapy (CT). The COMET study, conducted in France, described the characteristics of pts with metastatic CRC (mCRC) treated with raltitrexed, focusing on pts with cardiotoxicity or disease progression with prior 5-fluorouracil (5FU)/folinic acid. Methods: A national, multicentred, cross-sectional, non-interventional study to describe the profiles of pts with mCRC treated with raltitrexed. Pts (≥18 years) with mCRC, treated with raltitrexed as a single agent or in combination therapy, were included. Following patient consent, retrospective data were recorded during a single inclusion visit based on pt medical files; during the study, data were recorded prospectively. Results: 414 pts with mCRC were analysed; 84.8% had ≥1 prior CT, 60.9% had CV risk factors and 35.2% had CV history (angina: 11.8%; myocardial infarction: 11.8%). Overall, 79.5% of pts had received a prior 5FU-based CT. Reasons for switching to raltitrexed included short 15-min infusion duration (34.8%), treatment failure (49.8%) and acute cardiotoxicity with 5FU (8.9%). After switching, 57.2% of pts received raltitrexed as combination therapy. Mean initial dosage of raltitrexed was 2.6±0.6 mg/m2. Of those who had CV risk factors (n=73) or CV history (n=67), 69.0% and 72.7% received raltitrexed after CV toxicity, respectively. Of the pts treated with second-line raltitrexed and assessed with prior acute CV events (45/414), 88.9% (40/45) had no cardiac toxicity during treatment with raltitrexed. Of those (n=206) receiving raltitrexed due to treatment failure, 62.7% had received 5FU/folinic acid during their last CT. Of the pts assessed for tumour response (183/206), tumour progression was controlled with raltitrexed in 25.7% of cases (stable disease: 18.0%; partial response: 7.7%; progressive disease: 56.3%). Conclusions: Raltitrexed appears to be effective in heavily pretreated pts with mCRC and tumour progression after 5FU therapy and could be a safe therapeutic alternative to 5FU for pts with mCRC and prior cardiac toxicity.
Statin use and mortality in patients with colorectal cancer: A systematic review and meta-analysis of observational studies.
Authors: Gupta Arjun , Singh Siddharth , Singh Preet Paul
Published: February 2017

686

Background: Preclinical evidence suggests that statins have anti-neoplastic properties by inhibiting cell proliferation, and inducing apoptosis. Statins may be associated with reduced risk of colorectal cancer (CRC), but their effect on CRC related mortality is unclear. We performed a meta-analysis of published observational studies evaluating statin use in patients with CRC and its association with overall and CRC-specific mortality. Methods: Through a systematic search upto August 2014, we identified 7 observational studies (64,773 patients with CRC;19.5% statin users) reporting the association between statin use and mortality in patients with 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, statin use was associated with a 26% reduction in all-cause mortality in CRC patients as compared to non-use (6 studies; adjusted HR, 0.74; 95% CI, 0.67-0.83) with minimal heterogeneity (I2=18%), after adjusting for age, sex and CRC stage. Only one study adjusted for concomitant metformin use. Five studies evaluated CRC-specific mortality; on meta-analysis, use of statins (vs non-use) was also associated with decreased CRC-specific mortality (adjusted HR, 0.74; 95% CI, 0.70-0.83; minimal heterogeneity, I2=17%). On limiting analysis to statin use after diagnosis of CRC, use of statins remained significantly associated with reduced CRC-specific mortality (3 studies; adjusted HR, 0.70; 95% CI, 0.60-0.81), but not overall mortality (4 studies; adjusted HR, 0.82; 95% CI, 0.64-1.05). On restricting analysis to studies, which adjusted for concomitant use of aspirin/NSAID, the inverse association between statin use and overall- (5 studies; adjusted HR, 0.74; 95% CI, 0.66-0.84) and CRC-specific mortality (4 studies; adjusted HR, 0.76; 95% CI, 0.69-0.84) remained significant. Conclusions: Based on this meta-analysis, statin use in patients with CRC may be associated with reduced all-cause and CRC-specific mortality. This observation merits prospective investigation of statins’ effect on outcome in CRC patients.
Survival for patients with resectable lung metastatic colorectal cancer (mCRC).
Authors: Price Timothy Jay , Tomita Yoko , Beeke Carol , Padbury Robert , Townsend Amanda Rose , Maddern Guy , Roy Amitesh , Roder David , Karapetis Christos Stelios
Published: February 2017

708

Background: Hepatic resection for CRC metastasis is now considered a standard of care and perioperative chemotherapy may improve outcomes. Resection of metastasis isolated to lung is also considered potentially curable, although there is still some variation in recommendations and no evidence for perioperative or adjuvant chemotherapy. Here, we explore patient characteristics and outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. Methods: SA mCRC registry data were analysed to assess patient characteristics and survival outcomes between patients suitable for lung or liver resection. K-M survival analysis was used to assess OS. Results: 3,241 patient are registered on the database. 102 (3.1%) patients were able to undergo a lung resection compared to 420 (12.9%) a liver resection. Of the lung resection patients, 21% initially presented with liver only disease, 11% both lung and liver, and 7% brain or pelvic disease. 62 (61%) presented with lung only disease. Of these patients, 79% went straight to surgery and 34% had lung resection as the only intervention. When comparing the groups, they were balanced for age and sex, liver v lung; 67.7 years v 69.5 years, 63.6% v 57.8% male. There was no difference in pathological grade or KRAS MT rate when tested (36% liver v 32% lung). Compared to patients undergoing liver resection, those having lung resection were more likely to be metachronous (75.5% v 44%, p=<0.0001) and have a rectal primary (43.1% v 30.7%, p=0.017). Chemotherapy for metastatic disease was given more often in liver resection patients (76.9% v 53.9%, p=0.17). Median overall survival is not reached for both arms and the lower hazard rate for lung than liver resection does not approach statistical significance (HR 0.82, 95% CI 0.54-1.24, p=0.33). The 3 and 5 year survival liver v lung as follows; 77% v 81% and 62% v 70%. Conclusions: Lung resection occurs less frequently than liver resection for metastatic disease as expected. There was no statistical difference in overall survival in patients suitable for lung or liver resection. These data support the potential for long term survival with resection of both lung and liver metastasis in mCRC.
Repeated anti-CEA-radioimmunotherapy (RAIT) with 131iodine-labetuzumab after resection of colorectal liver metastases (CLM): Long-term results of a prospective phase II study.
Authors: Homayounfar Kia , Sahlmann Carsten O. , Niessner Martin , Meller Johannes , Conradi Lena-Christin , Dyczkowski Jerzy , Ghadimi B. Michael , Becker Heinz , Goldenberg David M. , Liersch Torsten
Published: February 2017

719

Background: Previously, single anti-CEA-radioimmunotherapy (RAIT) with 131iodine(I)-labetuzumab after complete (R0) resection of CEA-positive CLM was well tolerated and improved overall survival (OS) compared to a control group without RAIT. In this phase II study, we examined safety, feasibility, and long-term efficacy of repeated RAIT in the same setting. Methods: After R0-resection of CEA-positive CLM, 63 pts (42 m, 21 f; median age, 64.5 yrs) with synchronous (n=33) or metachronous (n=30) CLM received RAIT with 40-50 mCi/m2 per dose. 45 pts were intermediate/high risk for early metastatic relapse according to the Fong score. Restaging with CT/MRI and FDG-PET was performed prior to each RAIT. Pts with persistent elevated serum CEA-levels or inconclusive lesions during post-operative restaging received RAIT, but were classified as “non-adjuvant.” Toxicity was classified according to NCI-CTC v2.0. Time to progression (TTP), OS and cancer-specific survival (CSS) were calculated. The median follow-up was 54 (range 6-127) mos. Results: After the first cycle of RAIT 14 of 63 pts experienced grade 4 hematological toxicity. Nineteen pts did not receive the second cycle of RAIT due to prolonged toxicity, impaired performance status (n=6), or metastatic relapse (n=13). The latter were further treated by resection (n=3) or systemic chemotherapy (n=10). Forty-four pts received the planned second cycle of RAIT. Of these, 4 pts newly experienced grade 4 hematological toxicity. For all 63 pts, the median TTP, OS and CSS were 13, 57 and 92 months, respectively. The truly “adjuvant” pts (n=39) had a an improved median TTP (26 vs. 6.6 mos, p<0.0001), OS (76 vs. 42 mos, p=0.03) and CSS (not reached vs. 42 mos, p=0.003) in comparison to “non-adjuvant” pts (n=24). Conclusions: Repeated anti-CEA-RAIT with 131I-labetuzumab is safe, feasible, and well-tolerated (100% compliance), with expected hematological toxicity. The long-term survival after RAIT is very encouraging, in particular for pts deemed truly “adjuvant” post-salvage resection of CLM at restaging prior to RAIT.
Identifying variables influencing the efficiency and efficacy of a multidisciplinary team meeting.
Authors: Basta Yara L. , Baur Onno L. , van Dieren Susan , Klinkenbijl Jean H. G. , Tytgat Kristien M. A. J.
Published: February 2017

730

Background: Multidisciplinary team meetings (MDM) provide a platform for discussing diagnoses and treatments. Since many healthcare settings have accepted multidisciplinary care as best practice, avenues towards improving MDMs should be investigated. This study aimed to identify variables that influence the efficiency and efficacy of an MDM in a tertiary referral center in the Netherlands. Methods: Consecutive MDMs for hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), esophageal and gastric cancer (ESOGAS) and pancreatobiliary and liver cancer (HPB) were studied. Efficiency was measured as duration of the MDM. Efficacy was assessed by accurate diagnoses. Logistic and linear regression models identified variables influencing the efficiency and efficacy. Results: In 74 MDMs with a mean duration of 63 min (SD 14), 700 patients were discussed of which 114 patients at ≥2 MDMs. A median of 10 patients was discussed per MDM (IQR 6 – 14). Mean discussion time per patient was 05:19 min (SD 2). Corrected for tumor type, the number of patients discussed and the presence of others (e.g., research fellows) in addition to medical specialists, prolonged the MDM (+1.9 min CI 1.2 – 2.6; +0.64 min; CI 0.23 – 1.5 resp.). Including a follow up patient in the MDM, decreased the duration by 3.9 min (CI -5.8 – -2.0). The diagnostic accuracy of the MDM was 95%. The duration of the MDM or number of patients discussed did not influence this (OR 1.1 CI 0.99 – 1.0; OR 0.92 CI 0.79 – 1.1 resp.). The diagnosis was accurately altered for 117 (21%) patients, for 1 patient it was altered incorrectly. Tumor type predicted the accurate diagnoses (OR 0.1 CI 0.02 – 0.71; OR 2.0 CI 0.46 – 8.6; OR 3.1 CI 1.3 – 7.4; for HCC, CRC and ESOGAS respectively. Reference group: HPB). A correct diagnosis was more likely if patients’ cases were presented by their own doctor (OR 5.0 CI 2.0 – 12.5). Conclusions: MDMs play a crucial role in oncology management. For 21% of patients the diagnosis was correctly altered by the MDM. The diagnostic accuracy of the MDM was 95%. The absence of a presenting doctor decreased this accuracy while duration of MDM and number of patients discussed did not affect this accuracy. The presence of research fellows prolonged the duration of the MDM.
Prevalence and outcomes of patients (pts) with EGFR S492R ectodomain mutations in ASPECCT: Panitumumab (pmab) vs. cetuximab (cmab) in pts with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC).
Authors: Price Timothy Jay , Newhall Kathryn , Peeters Marc , Kim Tae Won , Li Jin , Cascinu Stefano , Ruff Paul , Suresh Attili Venkatasatya , Thomas Anne , Tjulandin Sergei , Boedigheimer Michael , Zhang Kathy , Sidhu Roger , Murugappan Swaminathan
Published: February 2017

740

Background: Mutations resistant to anti-EGFR treatment (tx), beyond those in RAS, have been reported and include EGFR S492R. We report results for pts with EGFR S492R mutations in the phase 3 ASPECCT trial. Methods: Pts were randomized 1:1 to receive pmab or cmab. Crossover was not allowed. The primary endpoint was non-inferiority of overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. EGFR S492R was evaluated by digital droplet PCR in plasma samples collected pre-tx and post-tx (safety follow-up 4 wks after the last dose). Outcomes were analyzed by EGFR S492 status. Results: Of 999 pts randomized and treated, post-tx samples were available for EGFR S492 assessment from 53% of pts (261/496) in the pmab arm and 57% of pts (285/503) in the cmab arm. EGFR S492R was detected in 1% of pts in the pmab arm and 16% of pts in the cmab arm in post-tx samples. EGFR S492R was not detected in pre-tx samples. Results are shown (table). Conclusions: In a retrospective analysis of pts with available samples from ASPECCT, 16% of pts in the cmab arm and 1% of pts in the pmab developed EGFR S492R mutations. Pts with EGFR S492R in the cmab arm had longer tx duration before progressive disease (PD) and appeared to have worse OS vs pts with wild-type S492 in the cmab arm. Clinical trial information: NCT01001377. [Table: see text]
Impact of CGA in therapeutic decisions: ELDERLY trial.
Authors: Gallego Plazas Javier , Asensio Martinez Elena , Lozano Inmaculada , Ricote Guillermo , Ore Martin , Cotes Almudena , Magdaleno Alejandra , Ors Mamen , Baron Jose M. , Campello Eric , Guaraz Patricia , Fernandez Silvia , Martinez Natividad
Published: February 2017

759

Background: Based on results from phase III clinical trials chemotherapy treatment benefit in patients ≥70 years old with stage III and IV colorectal cancer (CRC III-IV) is a subject in question. The ELDERLY trial aims to explore in a pilot program viability and convenience of an evidence based protocol for Comprehensive Geriatric Asessment (CGA) as well as the contribution of further evaluations. Methods: Patients ≥70 years old with CRC III-IV were prospectively and consecutively included. After initial treatment recommendation was made, study protocol for CGA (functional, nutritional, cognitive, social, psychological, and comorbidities) was carried out. Based on CGA, early death risk prediction model and chemotherpy toxicity risk stratification subsequent final treatment recommendation was obtained. Follow up of patients and comparison to historical controls is underway. Results: 20 patients (10 CRC III, 10 CRC IV), median age 79.2 years (71-85), 65% males, were included. ECOG PS was: 0 in 35% of patients, 1 in 35%, 2 in 20%, and 3 in 10% of patients. Initial treatment recommendation was: standard for 60% of patients, adapted standard for 25%, and no treatment for 15% of patients. According to Köhne et al. (Oncologist 2008) fitness categories 25% of patients were in group I, 55% in group II, and 20% of patients in group III. Early death risk, according to Soubeyran et al. (J Clin Oncol 2012), was high for 5% of patients. Chemotherapy toxicity risk, according to Hurria et al. (J Clin Oncol 2011) was low for 15% of patients, intermediate for 60%, and high for 25% of patients. Final treatment recommendation was: standard for 25% of patients, adapted standard for 55%, and no treatment for 20% of patients. Initial and final treatment recommendation diverged in 55% of patients (more conservative final treatment recommendation in 45%, and more intense final treatment recommendation in 10%). Conclusions: Evidence based protocol CGA modified initial treatment recommendations. Follow up of patients and comparison to historical controls could contribute to improve the knwoledge and convenience of this and further evaluations.
Safety and efficacy of adjuvant modified FLOX for patients (pts) with stage III colorectal cancer (CRC) treated in the community.
Authors: Protasio Bruno Mendonca , Matutino Adriana Reis Brandao , Lage Liana Valente , De Santana Iuri Amorim , Ramos Ricardo Emanuel De Oliveira , Caires-Lima Rafael , Caires Inacelli Queiroz De Souza , Riechelmann Rachel Pimenta , Saragiotto Daniel Fernandes , Sabbaga Jorge , Hoff Paulo Marcelo
Published: February 2017

760

Background: Based on the NSABP-C07 trial, FLOX became one of the standard adjuvant regimens for pts with stage III CRC. However, its efficacy and safety have not been evaluated outside of clinical trials. Methods: Retrospective analysis of all consecutive stage III CRC pts who received adjuvant chemotherapy with modified FLOX (5-FU bolus 500 mg/m2 and bolus of LV 20 mg/m2 for 6 consecutive weeks and oxaliplatin 85 mg/m2 in 2 hours-infusion at weeks 1, 3 and 5, every 8 weeks). Logistic regression (LR) multivariable models were used to identify predictors of relapse at 2 years and factors associated with grade ≥3 toxicity. Two-sided p<0.05 were significant. Results: From Feb 2007 to Oct 2013, 267 pts were eligible: median age was 59 years, 53.2% were male and 83 (32.2%) were operated emergently. Most pts (68.2%) had stage IIIB CRC, with a median of 21 (range: 1-119) lymphnodes resected. Pathology characteristics: 32 (12%) were poorly differentiated, 132 (49.4%) had angiolymphatic invasion and 75 (28.1%) had perineural invasion. Median time to chemotherapy initiation was 63 days (range: 10-188). With a median follow-up of 24 months, 67 (25.1%) pts recurred. In LR, urgent surgery (odds ratio [OR]=1.9, 95% IC: 1.03-3.49; p=0.039), angiolymphatic invasion (OR=1.99, 1.09-3.64; p=0.024), and delay/dose reduction of chemotherapy (OR=2.62; 1.45-4.72; p=0.001) were predictors of recurrence at 2 years. Any grade ≥3 toxicity occurred in 98 (36.7%) pts, with diarrhea (16.1%), and neutropenia (15.3%) being the most frequent ones. A total of 9 (3.4%) pts died from any cause within 60 days of starting modified FLOX. Age ≥65 years (OR=2.6, 1.26-5.38; p=0.01) was associated with a higher risk of grade ≥3 toxicity in LR. Conclusions: The adjuvant modified FLOX was effective in stage III CRC pts treated in the community but offered significant risk of serious toxicity and death. This regimen should be probably restricted to fit pts who are ≤65 years. Also, similar to the stage II setting, we found that stage III CRC pts whose primary tumor were ressected emergently, those with angiolymphatic invasion or who received less dose-intense chemotherapy were at higher risk of recurrence.
Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.
Authors: Amin Manik , Desai Monica Dandona , Sorscher Steven , Lim Kian-Huat , Wang-Gillam Andrea , Tan Benjamin R. , Picus Joel , Highkin Maureen , Lears Kimberly , Lockhart Albert C.
Published: February 2017

763

Background: Despite clinical success of VEGF blockade in mCRC, resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in resistance development to anti-angiogenic therapy. Levocetirizine is a third generation antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850mg/m2 – 7 days on and 7 days off, IV bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily in 14 day cycles. The primary end point was PFS and secondary endpoints included ORR and tolerability. An exploratory endpoint included correlation of PFS with cytokine (IL-8 & IL-6) levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To document cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy or to Arm B where levocetirizine was started 7 days prior to chemotherapy. For PFS determination both arms were combined for analysis. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). Results: 43 patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 20 patients and Arm B enrolled 23 patients. Of the patients evaluable for best response, 19 had SD and 12 had PD. Median PFS of all patients on the study was 3.4 months (ranging 0.9 to 10.6 months). Conclusions: Median PFS in the trial was comparable to and possibly better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine analysis is in progress and these results and correlations with patient outcomes will be presented to assess the impact of cytokine blockade on mCRC treatment. Clinical trial information: NCT01722162.
Tumor response assessment by measuring the single largest lesion per organ in patients with advanced gastric cancer or colorectal cancer.
Authors: Kim Jung Han , Jang Hyun Joo , Kim Hyeong Su , Song Hun Ho , Zang Dae Young
Published: February 2017

766

Background: The Response Evaluation Criteria in Solid Tumors Guidelines version 1.1 (RECIST 1.1) adopted a total of five target lesions to be measured, with a maximum of two lesions per organ. To the best of our knowledge, the criterion of two target lesions per organ in the RECIST 1.1 is arbitrary and has not been supported by any objective evidence. We hypothesized that measuring the single largest lesion in each organ (modified RECIST 1.1; mRECIST 1.1) might show almost the same response classification as measuring two target lesions per organ (RECIST 1.1). Methods: We compared tumor responses according to the modified RECIST 1.1 and RECIST 1.1 using computed tomography in patients with advanced gastric cancer (GC) or colorectal cancer (CRC) who received a first-line chemotherapy. Results: A total of 89 patients who had at least two target lesions in any organ according to the RECIST 1.1 were included: 51 with GC and 38 with CRC. Regardless of the primary sites, the number of target lesions according to the modified RECIST 1.1 was significantly lower than that according to the RECIST 1.1 (p < 0.001). The assessment of tumor responses showed a high concordance between the two criteria, with a kappa value of 0.906 (95% CI, 0.826-0.986). Only five patients (5.6%) showed disagreement in the tumor response assessment between the two criteria: 3 in GC and 2 in CRC. Four patients showed disagreement between PR and SD, and one showed disagreement between SD and PD. The overall response rates of chemotherapy, which were calculated regardless of the primary sites and anti-cancer treatment, were not significantly different between the two criteria (42.7% versus 42.7%, p = 1.0) (Table). Conclusions: The modified RECIST 1.1, with a decreased number of target lesions, was comparable to the original RECIST 1.1 in the assessment of tumor response in patients with advanced GC or CRC. Our results suggest that it may be possible to measure the single largest lesion per organ for assessing tumor response. [Table: see text]
Assessing alternative dosing strategies for granulocyte-colony stimulating factor (G-CSF) use with FOLFOX6 therapy for treatment of colorectal cancer in a prospective cohort.
Authors: Stinson Jordan , Ko Yoo-Joung , DeAngelis Carlo , Giotis Angie , Pasetka Mark
Published: February 2017

771

Background: While clinical guidelines recommend an average of 11 injections of granulocyte-colony stimulating factor (G-CSF) per cycle of chemotherapy, few studies support alternative dosing strategies for G-CSF use by cancer type and chemotherapy regimen. Methods: From 2004 to 2013, 63 colon and 47 rectal cancer patients were recruited and monitored throughout the course of their FOLFOX6 therapy. G-CSF use was determined by a clinical pharmacist and tracked every week to ensure patients received an adequate number of injections and were compliant with each cycle. All patients received at least two cycles of G-CSF. Occurrence of neutropenia, febrile neutropenia, and thrombocytopenia were compared between patients receiving four and five injections per cycle. Results: There were 54 males and 56 females with a median age of 56. 104 patients received adjuvant chemotherapy with the remaining six being in the metastatic setting. 83 of 110 (75%) patients experienced no delays after initiation of G-CSF with 67 (61%) of those patients receiving four or five injections per cycle. The remaining 27 of 110 (25%) patients experienced a delay in treatment after at least one cycle of G-CSF completed (15 neutropenic delays, four FN delays, and 12 thrombocytopenic delays). Significantly, only seven of those 27 (26%) patients had a neutropenic delay that occurred as a result of a failed dosing strategy after G-CSF was initiated. Of these seven neutropenic delays, five (71%) were the result of a four dose injection pattern, but none were the result of the five dose injection pattern scheme. All other delays, after at least one cycle of G-CSF (74%), were caused by patients’ non-compliance The overall compliance rate with G-CSF injections was 93%. Conclusions: Only 7 of 110 (6.4%) patients experienced a G-CSF failure. It is recommended that G-CSF be administered on day 4, 6, 8, 10, and 12 of each FOLFOX6 cycle to maintain absolute neutrophil counts and prevent treatment delays.
Perioperative management of esophageal cancer surgery based on a modified ERAS protocol.
Authors: Ogata Takashi , Makuuchi Yousuke , Segami Kenki , Kawabe Taiichi , Hayashi Shigeya , Sato Tsutomu , Osaka Yoshiaki , Tatibana Shingo , Tsuchida Akihiko , Cho Haruhiko , Yoshikawa Takaki
Published: February 2017

99

Background: We have performed perioperative management using modified ERAS protocol after esophageal cancer surgery. Our protocol includes plaque control in collaboration with dental clinic, breathing training, nutrition support for low-nutrition, preoperative oral rehydration, pain control, early mobilization, early enteral nutrition and intestinal peristalsis monitoring by abdominal Xp with contrast agents after surgery, and so on. Methods: The aim of the study is to clarify the safety of our modified ERAS protocol as perioperative management of esohphageal surgery. 136 cases of thoracic esophageal cancer patients were performed with 3 field lymph node dissection between January 2011 and July 2014 using modified ERAS protocol(group A). 29 cases were performed classical postoperative management between September 2008 and November 2009(group B). We compared ventilator weaning dates, start dates of postoperative ambulation, start dates of enteral feeding, start dates of oral intake, length of hospital stay, the number of hospital death between group A and group B. Results: In group A, except two cases was extubated in POD1, start dates of postoperative ambulation was POD1(median), start dates of enteral feeding was POD1(median), start dates of oral intake was POD6(median), length of hospital stay was 15days(median), and the number of hospital death was 1case. On the other hand, in group B, dates of extubation was POD4(median), start dates of postoperative ambulation was POD2(median), enteral feeding was not sued for postoperative management, start dates of oral intake was POD15(median), length of hospital stay was 29days(median), and the number of hospital death was 2case. After introduction of this protocol, all these values were significantly reduced in group A rather than in group B. Walking distance were 130m(POD1), 322m(POD2), 509m(POD3), completion rate of enteral feeding was 90%, and the safety of enteral nutrition was also confirmed by peristalsis monitor using abdominal Xp with contrast agents or defecation state. Conclusions: It was considered that perioperative management of esophageal cancer surgery based on modified ERAS protocol is contribute to the early recover of postoperative status.
Sensitivity of cytology and immunohistochemistry for diagnosis of pancreaticobiliary cancer.
Authors: Burnett Atuhani S. , Bailey Joanelle , Oliver Joseph B , Ahalawat Sushil , Chokshi Ravi J.
Published: February 2017

TPS490

Background: Biliary strictures present a diagnostic challenge to differentiate benign disease from hepatopancreaticobiliary (HPB) malignancies. ERCP cytology is commonly performed in these patients; however, its sensitivity for diagnosis of HPB malignancy is poor (41.6%). Many adjunctive tests have been investigated to improve the sensitivity of HPB biopsies. In a recent meta-analysis by our group the best immunohistochemical (IHC) stains were a combination of IMP3, S100A4, and standard cytology. IHC stains for S100P and pVHL negativity were also helpful. Based on this meta-analysis we have designed a retrospective analysis of old cell block specimens to demonstrate the sensitivity and specificity of a combination IHC staining panel in detecting HPB maliganancies. Methods: Retrospective IHC staining will be carried out on old cell blocks from ERCP brushings and EUS-FNA. Expression of IMP3, S100A4, S100P, and pVHL will be determined. Using this panel as a combination we will determine its sensitivity and specificity on 200 patient samples. We will further determine how many stains are necessary to achieve maximum sensitivity by subtraction of data from one or more IHC stains followed by repeating sensitivity calculations. Finally, we will calculate the cost of conducting these tests and determine the cost-benefit ratio of employing these tests in the wider clinical setting. Conclusions: Overall we feel these studies will advance the precision with which clinicians can determine the presence of HPB malignancy in patients undergoing biopsy. This will ultimately lead to fewer patients with benign disease undergoing resection unnecessarily.