bluuebunny/crossref_metadata_2025 huggingface dataset:
Matched pair analysis of sequential short course radiotherapy and FOLFOX chemotherapy as preoperative therapy for rectal cancer compared to neoadjuvant long course chemoradiotherapy.
Authors: Youssef Fady , Markovina Stephanie Subasic , Khwaja Shariq S. , DeWees Todd A. , Hunt Steven R. , Tan Benjamin R. , Myerson Robert J. , Parikh Parag J. , Olsen Jeffrey R.
Published: February 2017

665

Background: A recently completed institutional phase II trial evaluated near-total neoadjuvant therapy (nTNT) for locally advanced rectal cancer using short course radiotherapy (SCRT) followed by four cycles of FOLFOX prior to total mesorectal excision (TME). A matched pair analysis is presented to compare clinical outcomes for nTNT with conventional chemoradiotherapy (CRT), TME, and postoperative chemotherapy (CT) for patients treated at our institution. Methods: 80 patients with cT3-4N0-2M0-1 rectal adenocarcinoma planned for resection of all tumor enrolled on a phase II study of preoperative SCRT (25 Gy to the involved mesorectum, 20 Gy to elective nodes, in 5 fractions) followed by four cycles of mFOLFOX6 before TME, with 6-8 cycles of adjuvant FOLFOX suggested. 69 patients with cM0 disease comprised the study cohort for this analysis. Patients treated with conventional CRT, followed by TME and adjuvant CT (63% ≥4 cycles adjuvant FOLFOX) were identified and matched 2:1 for exact cTNM stage. Kaplan-Meier with log-rank analysis was used to compare local control (LC), distant metastasis free survival (DMFS), disease free survival (DFS), and overall survival (OS), and two-tailed Mann-Whitney and Chi-squared tests used to compare cohort characteristics. Results: Median follow-up was 26 and 49 months for the study and control groups, respectively. Median age (57 vs. 55 years, p = 0.98) and distance from the anorectal ring (6 vs. 5 cm, p = 0.16) were similar for study and control groups, respectively. Pathologic complete response (pCR) and T-downstaging rates were 30% vs. 23% (p = 0.26) and 75% vs 50% (p = 0.001) in the study and match cohort, respectively. Actuarial 2-year LC (97% vs. 98%, p = 0.69) and OS (100% vs. 95% at 2 years, p = 0.57) were similar between the study and control groups, respectively. Two-year DMFS (94% vs. 80%, p = 0.016) and DFS (94% vs. 80%, p = 0.027) were significantly better in the study cohort. Conclusions: Controlling for institutional bias, exact cTNM stage, and tumor location, nTNT resulted in increased T-downstaging, superior DMFS and DFS, and similar LC and OS compared to conventional CRT.
Detection of actionable oncogene drivers alterations in HER2-amplified gastric cancer by next generation sequencing.
Authors: Gomez-Martin Carlos , Pazo Cid Roberto A. , Salud Antonieta , Fonseca Paula J. , Leon Ana , Galan MaCarmen , Visa Laura , Rivera Fernando , Alsina Maria , Plaza Carlos , Angulo Barbara , Hernandez Prieto Susana , Dominguez Carolina , Rodriguez Garcia Margarita , Del Valle Elena , Fernandez Soledad , Rojo Federico , Cuatrecasas Miriam , Lopez-Rios Fernando
Published: February 2017

67

Background: HER2 amplified cases are the only subset of gastric carcinoma (GC) patients with an approved targeted therapy (≈20%). In GC it is still unknown if there is a mutually exclusive pattern of mutations in major driver oncogenes. We performed a systematic search for targetable oncogenes in a cohort of HER2 amplified GC patients. Methods: 53 Formalin-fixed paraffin embedded samples from HER2 amplified GC patients (43 tumor and 10 normal samples) were selected for next generation sequencing (NGS). Before DNA extraction a macrodissection procedure was performed to guarantee at least 30% tumor in all cases. DNA samples were sequenced using the Ion Torrent Personal Genome Machine (PGM) sequencing platform (Life Technologies, Carlsbad, CA, USA). The Ion AmpliSeq Cancer Hotspot Panel v2 was used. This panel encompasses more than 2800 mutational hotspots of 50 oncogenes and tumor suppressor genes. Data were processed using the Ion Torrent platform-specific pipeline software Torrent suite v4.2. Moreover, sequencing data were analyzed with Ion Reporter software 4.2 to detect any copy number alteration of the genes included in the panel. Results: We successfully sequenced all samples. We identified 89 mutations in 12 genes (range from 1 ~ 9). The most frequent significant mutations included TP53 mutations (30), PI3KCA (3), SMAD4 (3), CDKN2A (4), CTNNB1 (3) and MET (3). Other mutations were found in KRAS, NOTCH, APC, and VHL genes. We also detected potential amplifications in the KRAS (4), EGFR (9), PI3KCA (11), AKT (6), FGFR (6), CDKN2A (4) and CDH1(8) genes. Among 43 tumor specimens, 86% of specimens harbored at least one genetic alteration, most of them linked to actionable mutations or amplifications Conclusions: Within HER2 amplified GCs, there are additional subsets with a potentially targetable oncogene. Future testing for these targets will benefit from including HER2 amplified GC patients Supported by the Spanish Ministry of Health, Fondo de Investigaciones Sanitarias grant PI11/01005 and European FEDER (PN I+D+I 2008‐20011).
Survival among metastatic colorectal patients in clinical trials compared to the real world.
Authors: Wang Ziwei , Hwang Lindsay , Murphy James Don
Published: February 2017

673

Background: Randomized clinical trials play a central role in clinical research though only a small fraction of patients partake in clinical studies. Questions thus arise regarding the generalizability of clinical trial results to the remainder of the population. This study evaluated whether patient survival from randomized clinical trials in metastatic colorectal cancer reflects real world outcomes. Methods: A Pubmed search was used to identify randomized phase III clinical trials of first-line treatment for metastatic colorectal cancer published between 2005 and 2010. We excluded secondary or pooled analyses, second-line treatments, non-metastatic patients, non-English language, and non-randomized studies. Thirty-one clinical trials met these criteria, comprised of 79 distinct clinical trial arms. Overall survival among clinical trial patients was compared to metastatic colorectal cancer patients within the Surveillance, Epidemiology, and End Results (SEER) program. Within SEER, we restricted the analysis time-period and age of patients to match the enrollment period and age of patients within each individual clinical trial. Results: The clinical trials enrolled a total of 16,614 patients. Among all clinical trial arms the median survival ranged from 6.7-62 months, 1-year survival ranged from 30-97%, and 2-year survival ranged from 6-88%. Compared to SEER, the median survival was higher in 95% of the individual clinical trial arms by an average of 5.4 months (p<0.0001). The 1-year survival was higher in 94% of the clinical trial arms by an average of 16.7% (p<0.0001). The 2-year survival was higher in 71% of the clinical trial arms by an average of 7.2% (p<0.0001). Conclusions: This study found substantially improved survival among clinical trial participants compared to patients in the SEER database suggesting that survival estimates from clinical trials may not generalize to the “real world.” Potential patient factors such as differences in underlying comorbidity, performance status, disease burden, as well as variation in treatment could not be addressed in this study, though these factors likely explain some of the observed survival differences.
Surgical management of the primary tumor in stage IV colorectal cancer: A validation study.
Authors: Ahmed Shahid , Pahwa Punam , Kanthan Selliah , Fields Anthony L.A. , Le Duc Minh , Haider Kamal , Reeder Bruce , Ahmed Osama , Alvi Riaz , Iqbal Nayyer , Abbas Tahir , Zaidi Adnan , Arnold Florence , Yadav Sunil , Sami Amer , Leis Anne
Published: February 2017

675

Background: The observational studies have demonstrated superior survival of patients with stage IV CRC who undergo surgical resection of the primary tumor (SRPT). Yet the results are not confirmed in the setting of a randomized controlled trial. Lack of randomization and failure to control the prognostic variables that affect survival including performance status (PS) are the major critiques to the findings of observational studies. Our group has demonstrated that SRPT improves survival of stage IV CRC patients, who were diagnosed between 1992-2005, independent of age and PS (Cancer. 2014;120:683). The current study is undertaken to validate our findings in patients who are treated with modern chemotherapy. Methods: A cohort of 569 patients with stage IV CRC diagnosed between 2006-2010 in Saskatchewan was evaluated. Cox regression model was used to adjust survival for important prognostic variables. Results: Median age was 69 years (59-95) and M:F was 1.4:1. 35% had ECOG PS of >1. 313 (55%) patients underwent SRPT. Median followup time was 11 months (inter-quartile range 2-26). 57.3% received chemotherapy, 91.4% received FOLFIRI or FOLFOX and 67% received anti-EGFR inhibitors and or bevacizumab. Median overall survival (OS) of patients who had SPRT and received chemotherapy was 27 months compared with 14 months if they did not have surgery (p<0.0001). Median OS of patients who received all active agents and had SPRT was 39 months (95% CI: 25.1-52.9). On multivariate analysis SRPT, hazard ratio (HR) for mortality of 0.44 (95% CI: 0.35-0.56), use of chemotherapy, HR 0.33 (95% CI: 0.26-0.43), metastasectomy, HR 0.43 (95% CI: 0.31-0.58), second line therapy, HR 0.50 (95% CI: 0.35-0.70), and third line therapy, HR 0.58 (95% CI: 0.41-0.83) were independently correlated with superior survival. Elevated alkaline phosphatase, (HR 1.50 (95% CI: 1.20-1.78), grade 3 tumor, HR 1.33 (95% CI: 1.10-1.62), leukocytosis, HR 1.32 (95% CI: 1.05-1.66), stage IVb disease, HR 1.31 (95% CI: 1.10-1.56), and ECOG PS>1, HR 1.30 (95% CI: 1.04-1.57) were correlated with inferior survival. Conclusions: Our study supports SRPT in patients with stage IV CRC who are treated with modern combination of chemotherapy and biologics.
Contact x-ray brachytherapy 50 kV (CXB) for organ preservation in T2 T3a-b rectal cancer: Lyon-Nice experience in 120 patients.
Authors: Doyen Jerome , Francois Eric , Frin Anne-Claire , Benezery Karen , Zhou Fuxiang , Romestaing Pascale , Chapet Olivier , Barbet Nicolas N. , Gerard Jean-Pierre
Published: February 2017

676

Background: Organ preservation (avoiding TME surgery) for T2 T3 a-b rectal cancer is a field of active clinical research. Contact X Ray CXB combined with external beam radiotherapy (EBRT) ± concurrent chemotherapy (CRT) is an attractive method to achieve clinical complete response (cCR) and consequently rectal preservation. We report an overview of 120 patients treated with CXB+EBRT over a 25 year period in Lyon since 1986 and then in Nice until 2012. Methods: Between 1986 and 2012, 120 patients presenting rectal adenocarcinoma T2 T3a-b (distal rectum: 87; middle rectum: 33) were treated with CXB +EBRT with conservative intent. In Lyon (1986-2001), 80 patients median age: 73y; T2:52; T3:28) risk were treated using CXB (80-110 Gy/3-4 fr/4-6 weeks) followed by EBRT (39 Gy/13 fr/18 days) and 192 Iridium implant boost (20 Gy). When cCR was achieved, close surveillance was proposed. In Nice (2002-2012), 40 patients (median age 81y; T2:22; T3:18) received CXB same regimen as in Lyon (using new Papillon 50 machine since 2009) + EBRT (45-50 Gy/5weeks) with concurrent chemotherapy (5-FU or Capecitabine). When cCR was achieved close surveillance was proposed or local excision (13 pts). Results: Median follow-up time 58 months in both groups. Local relapse occurred mainly in the 2 first years. Isolated lymph node recurrence <5%. Bowel function good or excellent when rectum preserved. Main clinical outcomes in table (some improved results in Nice possibly due to better treatment approach and patient selection). Conclusions: CXB with EBRT and concurrent capecitabine achieve safely high rate of cCR with organ preservation. The OPERA randomized trial will reproduce Lyon R 96 trial (Gerard JP, JCO 2004;22:2404) and test the superiority of CXB boost for organ preservation. [Table: see text]
Establishment and characterization of patient-derived tumor xenograft using gastroscopic biopsies in gastric cancer.
Authors: Shen Lin , Gao Jing , Zhu Yan , Tian Tiantian , Li Yan Yan , Li Na , Zou Jianling
Published: February 2017

68

Background: The patient-derived tumor xenograft (PDTX) model has become the most realistic model for preclinical studies. PDTX models of gastric cancer using surgical tissues are reported occasionally; however, the PDTX model using gastroscopic biopsy, which is presented in this study, is very rare. Methods: A total of 185 fresh gastroscopic biopsies of gastric cancer were subcutaneously transplanted into NOD/SCID (Nonobese Diabetic/Severe Combined Immunodeficiency) mice. The characteristics of PDTX were identified by hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), dual-color in-situ hybridization (DISH), and targeted next-generation sequencing. Chemosensitivity of PDTX model was tested using chemotherapy regimens based on patients. Results: Sixty-three PDTX models were successfully established (34.1%, 63/185) and passaged to maintain tumors in vivo, and the mean latency period of xenografts was 65.86±32.84 days (11-160 days). Biopsies of prior chemotherapy had a higher transplantation rate (52.1%, 37/71) than biopsies after chemotherapy (21.9%, 25/114; P<0.01). No differences were found between the latency period of xenografts and characteristics of patients. The pathological and molecular features of PDTX as well as chemosensitivity were highly consistent with those of primary tumors of patients. The genetic characteristics were stable during passaging of PDTX models. Conclusions: PDTX models using gastroscopic biopsies in gastric cancer were demonstrated for the first time, and the biological characteristics of the PDTX models were highly consistent with patients, which provided the best preclinical study platform for gastric cancer. [Table: see text]
Patterns of colorectal cancer care in the United States: 1990-2010.
Authors: Murphy Caitlin C. , Harlan Linda C , Lund Jennifer Leigh , Lynch Charles , Geiger Ann M.
Published: February 2017

684

Background: Colorectal cancer (CRC) incidence and mortality have declined in the U.S. over the past two decades. Much of the decline can be attributed to screening and advances in treatment. Few studies have evaluated the extent to which recommended therapies have been adopted in community settings and temporal changes in patterns of care. Methods: Patients diagnosed with stages II and III CRC were randomly sampled from the population-based Surveillance, Epidemiology, and End Results (SEER) program in 1990-91, 1995, 2000, 2005, and 2010 (n=7,056). Treatment data were obtained through medical record review and physician verification. We described the receipt of adjuvant chemotherapy among colon cancer patients and preoperative or postoperative radiation therapy among rectal cancer patients. Log-binomial regression was used to examine factors associated with receipt of therapy. Results: Receipt of adjuvant chemotherapy increased among stages II and III colon cancer patients from 1990 (stage II: 22%, stage III: 55%) to 2005 (stage II: 32%, stage III: 72%) and decreased in 2010 (stage II: 29%, stage III: 65%). Chemotherapy regimens changed over time; there was an increase in the use of capecitabine (3% in 2000 to 24% in 2010) and oxaliplatin (6% in 2000 to 79% in 2010). Stage III colon cancer patients who were older (75-79 years: RR 0.82, 95% CI 0.72, 0.94; ≥80 years: RR 0.36, 95% CI 0.27, 0.49) or had a comorbidity score ≥ 2 (RR 0.54, 95% CI 0.34, 0.86) were less likely to receive adjuvant chemotherapy. Receipt of radiation therapy among stages II and III rectal cancer patients increased across all study years from 46% to 66%, with a shift toward preoperative therapy in 2005. From 2005 to 2010, receipt of neoadjuvant chemoradiation followed by surgery and postoperative chemotherapy nearly doubled (11% in 2005 to 21% in 2010). Increasing age (75-79 years: RR 0.60, 95% CI 0.48, 0.75; ≥80 years: RR 0.34, 95% CI 0.25, 0.45) was associated with lower chemoradiation use in rectal cancer. Conclusions: Our findings demonstrate increased adoption of adjuvant therapies for both colon and rectal cancer patients and differences in therapy receipt by age, comorbidity, and diagnosis year. Improved receipt of adjuvant therapies in the community may further reduce CRC mortality.
Exceptional responses in patients with metastatic colorectal cancer enrolled in first-in-man studies from 2002 through 2012.
Authors: Patel Shiven B. , Tometich Danielle , Reese Zachary L , Sharma Sunil , Garrido-Laguna Ignacio
Published: February 2017

687

Background: Understanding exceptional responses to therapy at the molecular level may open new venues for the treatment of patients with metastatic colorectal cancer (mCRC). Responses in first-in-man (FIM) studies with targeted therapies are rare and may indicate that actionable genetic aberrations are present in these patients. Methods: We utilized Scopus using the search term “phase 1 and solid tumors” to collect all FIM studies published between 2002 and 2012. We identified patients with mCRC who attained an exceptional response to therapy defined as a complete response (CR) or a partial response (PR) lasting > 6 months (m). Results: We identified 118 FIM studies enrolling 5,369 patients with advanced malignancies. mCRC was the most common tumor type, totaling 1,055 (19.6%) patients. Of these, two patients enrolled in protocols with MDX-1106 (anti PD-1) and RG7180 (mAb EGFR) attained a complete response (CR). Five patients had PR lasting > 6 m. These patients were treated with RG7180 (time on study 7.8 m), Apatinib, a VEGFR tyrosine kinase inhibitor (8.5 and 7.1 m), PV701, a replication-competent oncolytic virus (10 m) and RO4929097, a gamma-secretase inhibitor (7 m). In addition two patients had PR lasting < 6 m with regorafenib (5.3 m) and RG7180 (5.6 m). This database of exceptional responders to therapy will be publicly available at Huntsman Cancer Institute website. Currently, regorafenib and EGFR mAbs (cetuximab and panitumumab) are approved for use in mCRC. EGFR mAbs have shown improvement in survival in RAS wild-type mCRC. Clinical trials are underway evaluating apatinib. Anti-PD1s have shown limited activity as single agents in mCRC and are currently undergoing testing in combination with chemotherapy. Conclusions: We identified exceptional responses among patients with mCRC enrolled in FIM in the last decade. Ongoing efforts are directed to conduct next generation sequencing (NGS) in archived tissue from these patients. Ultimately, this initiative may facilitate the identification of biomarkers of response to be tested in clinical trials with these or novel drugs sharing similar mechanisms of action.
Patient's self-reported adherence to capecitabine on XELOX as adjuvant therapy for colorectal cancer.
Authors: Kawakami Kazuyoshi , Yokokawa Takashi , Sugita Kazuo , Hagino Akane , Suzuki Kenichi , Oniyama Sayaka , Kohdo Satoshi , Machida Yohiaki , Suenaga Mitsukuni , Mizunuma Nobuyuki , Yamaguchi Tohiharu , Hama Toshihiro
Published: February 2017

690

Background: Capecitabine plus oxaliplatin (XELOX) has been established as adjuvant therapy for stage II/III colon cancer. Adherence to capecitabine is particularly important with XELOX to maintain appropriate curative effect. In this study, we monitored the adherence to capecitabine during adjuvant treatment with XELOX, and investigated the candidate factors that might decrease the adherence. Methods: The study included 139 consecutive patients who received XELOX treatment as adjuvant therapy for colorectal cancer between November 2011 and March 2014. Adherence to capecitabine was checked by pharmacists using a patient-reported treatment diary at a pharmaceutical outpatient clinic. Adherence rate was defined as the number of which a patient took capecitabine between d1 evening and d15 morning per 28 in each treatment cycle. The relative dose intensities and the deteriorating factors of adherence to capecitabine were retrospectively surveyed from electronic patient records. Results: 70 male and 69 female patients received adjuvant XELOX. Median adherence rate was 95.4% (n=139) in the first cycle of XELOX treatment, which gradually rose to 98.3% (n=121) in the eighth cycle. The median relative dose intensity of capecitabine was 76.7%. The main factors contributing to decreased adherence to capecitabine were diarrhea (34.7%) and nausea/vomiting (20.2%), peripheral neuropathy (10.7%). Conclusions: In this study, patient-reported adherence to capecitabine on XELOX treatment in clinical practice was highly maintained during all treatment cycles, and poor-adherence appeared to correlate with gastrointestinal events such as diarrhea, nausea, or vomiting. Our results suggest that assessment for compliance along with management of adverse events is needed to maintain treatment effect in clinical practice.
Phase I study of anti-CD3 x anti-EGFR–armed activated T-cells for treatment of advanced colorectal or pancreatic cancer.
Authors: Choi Minsig , Dyson Greg , Thakur Archana , Mahaseth Hemchandra , Philip Philip Agop , Shields Anthony Frank , Deol Abhinav , Lum Lawrence G.
Published: February 2017

698

Background: Advanced colorectal cancer (CRC) and pancreatic cancer (PC) are common gastrointestinal cancers with poor prognosis. Novel therapy with less toxicity using immune system is an attractive avenue for treatment. Preclinical studies have shown targeted tumor cell killing when anti-CD3 and anti-EGFR were heteroconjugated (EGFRBi) and added to cell cultures of colon cancer, lung cancer and breast cancer including tumor-xenograft models. Methods: Patients who have no standard treatment options with advanced CRC and PC were treated with immunotherapy. Peripheral blood mononuclear cells (PBMC) for the generation of armed activated T cells (ATC) was collected using 1 leukapheresis to obtain 8-20 x 109 PBMC for T cell expansion. The PBMC was activated with anti-CD3 monoclonal antibody (anti-CD3) and expanded in IL-2. ATC was harvested, armed with EGFRBi, and cryopreserved in aliquots for 4 infusions. The primary objective of the study was to determine the feasibility and safety of immunotherapy. Secondary endpoints were immune response, tumor response and overall survival. Results: The study accrued 13 patients with 10 patients receiving at least 3 weekly immunotherapy. In two patients (age 73 and 78) no viable cells were grown and one patient developed symptomatic brain metastasis after leukapharesis. Median age was 58 (50-78) and 8 patients had CRC and 5 patients had PC. Total of 34 billion activated T cells ( range 0-50 billions) were infused with no significant toxicity. Infusion related headache, fever, chills and blood pressure changes was most common adverse events and most of the symptoms resolved within 48 hours of infusion. No objective tumor regression was noted but stable disease was noted lasting 2.5 to 7.6 months. Among 10 patients treated with immunotherapy OS was 13.4 months while 3 patients who did not receive therapy was 5.4 months. Overall survival for all patients (n=13) was 11.4 months. Conclusions: Activated T-cells armed with anti-CD3 x anti-EGFR can be produced and infused in patients with advanced CRC and PC with minimal toxicity. Further studies in larger number of patient will test efficacy of this immunotherapy strategy (clinical trial info NCT01420874). Clinical trial information: NCT01420874.
Comprehensive genomic profiling (CGP) of advanced stage esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) to reveal similarities and differences.
Authors: Wang Kai , Chmielecki Juliann , Ali Siraj M. , Elvin Julia Andrea , Yelensky Roman , Lipson Doron , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S.
Published: February 2017

7

Background: ESCC and EAC are relatively rare malignancies in the US with EAC more common than ESCC. Using a sensitive CGP assay, we compared the genomic profiles of ESCC and EAC focused on the search for therapy targets. Methods: DNA was extracted from 40u of FFPE sections from 54 clinically advanced ESCC and 234 EAC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a median coverage depth of 652X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA) including point mutations, short INDELs, copy number alterations and fusions/rearrangements. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: All ESCC and EAC were at an advanced stage (Stage III/IV) at the time of CGP and had similar gender and age (median 63 yrs) distribution. 54 (100%) of ESCC and 233 (99.6%) of EAC featured GA on profiling with 397 GA in ESCC (7.4/sample) and 1,317 GA (5.6/sample) in EAC. The frequency of clinically relevant GA in ESCC (2.7/sample; 93% of cases) and EAC (2.7/sample; 92% of cases) were identical. EAC featured a greater number of CRGA (72) than ESCC (46). CRGA more frequently altered in EAC than ESCC included KRAS (23% vs 7%) and ERBB2 (23% vs 4%). CRGA more frequently identified in ESCC than EAC included PIK3CA (28% vs 10%), PTEN (13% vs 4%) and NOTCH1 (22% vs 3%). Other GA that were significantly different in the 2 tumor types included SMAD4 (14% EAC vs 0% ESCC), RB1 (19% ESCC vs 2% EAC), SOX2 (17% ESCC vs 1% EAC) and NFE2L2(19% ESCC vs 0% EAC). HPV-16 was detected in 2 (4%) and HPV-18 in 1 (2%) of ESCC. HPV was not detected in EAC. Conclusions: ESCC and EAC share high frequencies of total GA and CRGA. However, KRAS and ERBB2 are far more frequently altered in EAC than ESCC and mTOR pathway genes (PIK3CA and PTEN) more frequently altered in ESCC than EAC. CGP shows significant promise to identify CRGA in both ESCC and EAC and drive the potential use of clinical outcome altering targeted therapies in both major types of esophageal cancer.
siRNA library screening to define esophageal adenocarcinoma cell survival factors.
Authors: Duggan Shane P , Garry Catherine , Behan Fiona , Kirca Murat , MacGarrigle Sarah , Kudo Hiromi , Goldin Robert D , Botto Marina , Long Aideen , Kelleher Dermot P
Published: February 2017

70

Background: There is a pressing need to identify new therapeutic targets for esophageal adenocarcinoma (EAC). Hence, we utilized siRNA-screening libraries to identify genes impacting on EAC cancer cell growth to identify potential therapeutic targets. Methods: A “druggable genome” library (6,022 individual siRNAs) was utilized to examine EAC cell survival using the MTT assay. Statistical analysis combined the use of Z-factor, t-test and SSMD. EAC cell lines GohTRT, SKGT4 and OE33 were utilized. Functional validation of the resulting siRNAs utilized RT-PCR, Western Blot, ELISA and TOPFLASH assays. Results: siRNA library screening resulted in positive quality metrics (Z-factor>0.5) confirming its validity and further identifying 118 high confidence gene targets affecting EAC cell growth. Verification of these siRNA targets in multiple cell lines indicated a good level of concordance with the primary screening data. Bioinformatic and pathway mapping approaches of these targets emphasized links between EAC cell proliferation and regulators of inflammation and “immune cell processes” (LIF, C1Qa, C1r, C1s, GDF15, IL9R and TREM2). Pathological and transcriptomic studies demonstrated that LIF (FC=96.7; P<0.0001), GDF15 (EAC: FC=74; P<0.0001), C1Qa and TREM2 may be up-regulated in EAC biopsies. In functional work, exposure of EAC cell lines to recombinant or native proteins of C1q, LIF and GDF15 rescued the observed effects of their respective silencing in EAC cells (>90%,p0.001) and acted as potential growth promoters (>40%, p0.01). Auto-regulatory feedback loops were discovered in response to treatment with exogenous C1q and LIF in EAC cells. Signal transduction could be induced through b-catenin stabilization and STAT3 pathways in response to C1q and LIF treatment respectively. GDF15 was observed to act in a similar fashion to TGFb in scratch wound assays and additionally regulate Th17 type T-cell differentiation. Conclusions: Genes regulating EAC proliferation have been defined by siRNA library screening. We have identified secreted immune factors, not previously associated with EAC biology, capable of regulating EAC cell survival.
Benefit of adjuvant chemotherapy in patients with T4, UICC II colon cancer.
Authors: Teufel Andreas , Gerken Michael , Hartl Janine , Itzel Timo , Fichtner-Feigl Stefan , Stroszczynski Christian , Schlitt Hans J. , Hofstaedter Ferdinand , Klinkhammer-Schalke Monika
Published: February 2017

700

Background: Colorectal cancer is the third most common cancer and a major cause of morbidity and mortality worldwide. Adjuvant chemotherapy is considered standard of care in patients with UICC stage III colon cancer after R0-resection. For patients with UICC stage II colon cancer, a benefit of adjuvant therapy was not demonstrated. However, there is an ongoing discussion whether adjuvant chemotherapy may be beneficial for a subgroup of UICC II patients with "high-risk situation" (e.g., T4 situation). Methods: We investigated our Bavarian, population based (2.1 million inhabitants) cohort of 1,937 patients with UICC II CRC for a benefit of adjuvant chemotherapy in patients with larger (T4) tumors. Patients over 80 years were excluded. Of these patients, 240 patients had a T4 tumor (12%). 77 of all T4 patients received postoperative chemotherapy (33%). Survival analyses were performed using Kaplan Meier analysis and Cox regression models. Results: Patients with a T4 tumor who received postoperative chemotherapy had a highly significant survival benefit with respect to overall survival (p<0.001) and recurrence free survival (p=0.008). However, no difference was seen between oxaliplatin containing or non-oxaliplatin containing treatment regimens. Finally, G2 and G3 tumors were demonstrated to particularly benefit from adjuvant treatment. Chemotherapy, age at diagnosis and tumor grading remained independent risk factors in multivariable cox regression analysis. Conclusions: Overall, our retrospective study demonstrated a significant benefit of an adjuvant chemotherapy in the T4 UICC II subgroup of patients with colon cancer. Based on our data adjuvant chemotherapy should strongly be considered in these patients.
Phase I/II trial of IMMU-132 (isactuzumab govitecan), an anti-Trop-2-SN-38 antibody drug conjugate (ADC): Results in patients with metastatic gastrointestinal (GI) cancers.
Authors: Starodub Alexander , Ocean Allyson J. , Messersmith Wells A. , Picozzi Vincent J. , Guarino Michael J. , Thomas Sajeve Samuel , Bardia Aditya , Shah Manish A. , Govindan Serengulam V. , Maliakal Pius P , Wegener William A. , Hamburger Steven A. , Sharkey Robert M. , Goldenberg David M.
Published: February 2017

703

Background: Trop-2 is a tumor-associated glycoprotein highly expressed in many epithelial cancers. Elevated expression has been linked to more aggressive disease and a poorer prognosis. IMMU-132 is an ADC comprising a humanized mAb binding to Trop-2 and conjugated to SN-38 (drug: Ab ratio = 7.6), the active metabolite of irinotecan. After finding potent activity in human tumor xenografts, a phase I/II trial was undertaken (NCT01631552). Methods: Pts with relapsed/refractory metastatic cancers were enrolled, starting at a dose of 8 mg/kg given on days 1 and 8 of a 3-week cycle. Dose levels of 8 and 10 mg/kg were chosen for phase II (N=47). Results: Sixty pts with advanced GI cancers were enrolled in phase I/II. Neutropenia was the principal dose-limiting toxicity, with fatigue, diarrhea, nausea, and vomiting as other reported toxicities. In the phase II pts with median prior therapies of 3 (range 1-7), the following moderate/severe drug-related toxicities occurred: neutropenia (Gr 3, 18.8%; Gr 4, 10.4%); fatigue (Gr 3, 14.6%; Gr 4, 0%), anemia (Gr 3, 10.4%; Gr 4, 0%); diarrhea (Gr 3, 4.2%; Gr 4, 0%). Of 29 CRC pts (10 mg/kg [N=9], 8 mg/kg [N=20]), 1 had a PR and 14 had SD as the best response by RECIST, with a time to progression (TTP) of 11.5+ months (mo) for the PR (65% shrinkage) and a median of 4.8+ mo for the SD pts (5 ongoing). This is a disease control rate (DCR) of 51.7%. Thirteen CRC pts had KRAS mutations, 7 with SD (median TTP = 4.4+ mo [range, 2.8-7.8 mo; 3 ongoing]). Of 15 pts with pancreatic ca, 8 had SD as best RECIST response (median TTP = 3.4 mo); DCR=53.3%. Among 11 pts with esophageal ca, 7 had CT assessments with 1 PR (TTP, 6.9+ mo), and 4 SD (TTP, 4.0+, 5.0, 6.0, and 6.9 mo) as best response; DCR=62.5%. Of 5 gastric ca pts, only 3 had post-baseline CT assessments, all with SD (1 with 19% target lesion reduction and an ongoing TTP of 6.7+ mo). Conclusions: IMMU-132 is a novel anti-cancer therapeutic, conjugating a topoisomerase I inhibitor to an internalizing, cancer-selective mAb. This ADC can be given safely and repeatedly over many months to heavily pretreated patients. Encouraging activity in pts with several metastatic gastrointestinal tumors has been observed. Clinical trial information: NCT01631552.
Multicenter phase II trial of neoadjuvant chemotherapy with mFOLFOX6 for stage II/III rectal cancer with a T3/T4 tumor FACT trial.
Authors: Enomoto Toshiyuki , Saida Yoshihisa , Takabayashi Kazuhiro , Nagao Jiro , Koike Junichi , Funahashi Kimihiko , Yoshimatsu Kazuhiko , Yokomizo Hajime , Kan Hayato , Yamada Takeshi , Ishida Hideyuki , Ishibashi Keiichiro , Katsumata Kenji , Hasegawa Hirotoshi , Koda Keiji , Ochiai Takumi , Sakamoto Kazuhiro , Ogawa Shimpei , Itabashi Michio , Kameoka Shingo
Published: February 2017

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Background: The efficacy and safety of neoadjuvant chemotherapy with mFOLFOX6 for stage II/III rectal cancer patients with a T3/T4 tumor is still unknown. Methods: Inclusion criteriain this study are as follows: Stage II/III (Ra/Rb) rectal cancer patients with a T3/T4 tumor. The primary endpoint is preoperative response rate, and the secondary endpoints are histological effect, R0 resection rate, pCR rate, down-staging rate, neoadjuvant therapy completion rate, toxicity, the incidence of postoperative complications, and 3-year disease-free survival. Computed tomography was performed after 4 courses of mFOLFOX6. Patients with disease progression (DP) underwent resection of the primary lesion, while those without DP received another 2 courses of treatment. Treatment was discontinued when resection was not possible in patients with DP. Results: Registered patients totaled 53 with a mean age of 60 (38–77). The number of patients with T3 and T4 tumors was 42 and 10, and patients at stages II and III were 10 and 42, respectively. One patient withdrew due to consent retraction. Median relative dose intensity of mFOLFOX6 therapy was 93.2% for L-OHP, 5-FU, and l-LV. Treatment completion was achieved in 96.2% and 84.6% for 4 and 6 courses, respectively, and withdrawal was due to patient’s discretion, not adverse events. Preoperative response rate was 51%. Surgery was performed in 78.8% of patients. Serious (grade ≥3) toxicity included neutropenia (n=5), leukopenia (n=1), thrombocytopenia (n=1), febrile neutropenia (n=1), nausea (n=1), vomiting (n=1), and peripheral neuropathy (n=2). The rates of R0 resection, pCR, and sphincter preservation were 91.0%, 10.3%, and 82.9%. The down staging rate was calculated as 2%. The median follow-up after surgery was 18.0 months. Median DFS was 17.3 months, and 1-year disease-free survival was 78.8%. Median OS was 22.0 months, and 1-year overall survival was 95.7%. Postoperative complications included suture failure (n=3), wound infection (n=2), pneumonia (n=1), and intestinal obstruction (n=1). Conclusions: Neoadjuvant chemotherapy using mFOLFOX6 is a safe and efficacious treatment option for rectal cancer, especially locally advanced disease. Clinical trial information: UMIN000006583.
Risk factors for postoperative complications of a randomized clinical trial: Laparoscopic versus open surgery with D3 lymphadenectomy for stage II/III colon cancer (JCOG0404).
Authors: Nishizawa Yusuke , Ito Masaaki , Saito Norio , Katayama Hiroshi , Mizusawa Junki , Yamaguchi Takashi , Masaki Tadahiko , Fukunaga Yosuke , Murata Kohei , Akagi Tomonori , Inomata Masafumi , Kitano Seigo
Published: February 2017

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Background: A randomized controlled trial to confirm the non-inferiority of laparoscopic surgery to open surgery for clinical stage II/III colon cancers in terms of overall survival was conducted. In this ancillary study, we explored the risk factors for postoperative complications of laparoscopic surgery and open surgery. Methods: Eligibility criteria included colon cancer; tumor located in the cecum, ascending, sigmoid, or rectosigmoid colon; T3 or T4 without involvement of other organs; N0-2; and M0. Postoperative complications which were observed from the end of the operation to discharge were graded according to the CTCAE 3.0. Multivariate analysis was performed using logistic regression model. Results: Between October 2004 and March 2009, a total of 1,057 patients from 30 Japanese centers were registered. By per-protocol set, 524 patients underwent open surgery (OPEN) and 533 patients underwent laparoscopic surgery (LAP). Proportion of any grade (G) complication was 18.3% (OPEN 22.3%, LAP 14.3%), G2–G3 was 12.9% (OPEN 13.9%, LAP 11.8%), G3 was 5.3% (OPEN 6.9%, LAP 3.8%) and G4 was none. Postoperative complications (G2-G3) included leakage (OPEN 2.1%, LAP 1.9%), ileus (OPEN:1.5%, LAP:0.9%), and wound complication (OPEN: 0.2%, LAP: none). Multivariate analysis revealed that risk factors for postoperative complications were operation times 240 min or more (p=0.0019, odds ratio [OR] 2.01 [95% CI: 1.30-3.13]) and open surgery (p=0.0001, OR 2.05 [95% CI: 1.41-2.98]). Conclusions: Operation times more than 240 min and open surgery were considered to be the risk factors for postoperative complications for clinical stage II/III colon cancers. Clinical trial information: C000000105.
Possible predictive clinical factors for chemotherapy holiday in metastatic colorectal cancer: A single institution–based retrospective data analysis.
Authors: Tumula Praveen Kumar , Tapan Umit , Hartshorn Kevan L.
Published: February 2017

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Background: During the last decade, numerous new agents were introduced into the therapy of metastatic colorectal cancer. For those patients who are not curable by resection, life can be extended with chemotherapy. However, it is not possible to predict who can safely take breaks without compromising survival. We sought to evaluate the relationship between various possible predictive factors and the duration of break from chemotherapy in patients with metastatic colorectal cancer. Methods: The hospital’s cancer registry was used to identify metastatic colon cancer cases diagnosed from January 2008 to December 2012. To be included in the study, the patient must have been diagnosed with colorectal adenocarcinoma, treated with a fluoropyrimidine based chemotherapy regimen and had planned treatment breaks. Retrospective chart review of electronic medical records was used to collect patient characteristics, including age, performance status (ECOG), comorbidities, disease burden (number of metastasis), and response to the initial treatment. Multivariate regression analysis was performed to observe impact of various variables on the duration of break from chemotherapy. Results: A total of 110 patients were diagnosed with metastatic colorectal cancer between 2008 to 2012 and 27 (24.5%) subjects in the initial analysis met the inclusion criteria, with a mean age of 56 years. The percentage of male and female patients was 37% and 63%, respectively. Patients who had a complete response to the initial chemotherapy (n=6) had 69±23 week breaks which was significantly longer (p<0.01) than the 17±2 and 13±5 week breaks of those with partial response or stable disease. In multivariate regression analysis, degree of response was a significant predictor for chemotherapy breaks (CI 0.36 – 1.77, p=0.005). No statistical difference was noted in other variables. Conclusions: These preliminary findings suggest that complete response to initial chemotherapy may be a strong predictor of patients who can safely undergo chemotherapy breaks. This study also raises the possibility that various factors could influence break from chemotherapy.
Tumor necrosis as prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer.
Authors: Jung Ji Han , Kim Hyung Jin , An Ho Jung , Kim Sung Whan , Cho Hyun Min , Shim Byoungyong
Published: February 2017

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Background: Association between treatment response on the basis of pathologic stage evaluated after radical tumor resection and patient prognosis was well established. The object of this study is that tumor necrosis factor after CRT is also important as treatment response. Methods: A total of 243 patients with locally advanced rectal cancer that underwent neoadjuvant CRT was included. Three treatment response groups were classified by their pathologic stage results: complete treatment response (CTR), intermediate treatment response (ITR), and poor treatment response (PTR). Three tissue necrosis groups were classified by tissue pathologic results: complete necrosis response (CNR), intermediate necrosis response (INR), and poor necrosis response (PNR). Results: Overall survival (OS) and recurrence free survival (RFS) rate at 3 years were 74.5% and 61.3%, respectively. The 3-year OS rates of the CTR, ITR, and PTR were 83.7%, 75.9%, and 69.7%, respectively (p<0.001); the 3-year RFS rates were 76.7%, 69.0%, and 52.1%, respectively (p<0.001). The 3-year OS rates of the CNR, INR, and PNR were 83.7%, 80.6%, and 61.8%, respectively (p<0.001); the 3-year RFS rates were 76.7%, 68.9%, and 44.3%, respectively (p<0.001). When compared to CTR / CNR, PTR / PNR was strongly related to an increased risk of recurrence (hazard ratio, 5.53; 95% CI, 2.01 to 15.23 / 6.37; 95% CI, 2.29 to 17.74) respectively in the univariate Cox regression. Therefore in the two models using multivariate Cox regression, both PTR and PNR were strongly associated to RFS and OS compared with CTR and CNR. Conclusions: The tissue response factor to neoadjuvant CRT is one surrogate marker for recurrence and oncologic outcomes and almost as important as the treatment response factor in rectal cancer patients treated with neo-adjuvant CRT.
Effect of neoadjuvant pelvic perfusion on symptom control and resection of pelvic recurrent rectal cancer.
Authors: Wanebo Harold J. , Begossi Giovanni J. , Gustafson Eric , Belliveau James
Published: February 2017

723

Background: Isolated pelvic perfusion (IPP) may improve disease control and facilitate pelvic resection in selected high-risk patients with advanced recurrent rectal cancer by reducing painful tumor burden and lessening chances of recurrence. Methods: IPP was done in 42 patients with locally advanced previously irradiated rectal cancer, 26 as preoperative therapy and 16 for palliation. A comparative larger non-perfused group included 63 patients with pelvic resection only via abdominal sacral resection (ABSR) for recurrent rectal cancer. Isolated pelvic perfusion (IPP) with a pump oxygenator, (temp > 41ºc), delivered sequential (q 10 minutes) chemotherapy:– 5FU (5fluorouracil) 1,500 mg/m2, cisplatin/oxaliplatin 100/150 mg/m2, mitomycin 10mg/m2, for 60 minutes in 42 patients. Results: Palliative IPP in 16 advanced rectal cancer patients resulted in significant relief (1–4 months) of narcotic resistant pain (in 70%). Pre-operative IPP in 26 locally advanced rectal cancer patients achieved a clinical path (CR) in 2 patients, and significant regression in 11 patients rendering them resectable. Seven had RO pelvic resections. Of 6 other patients, 4 refused surgery, 2 were medically excluded. Median survival was 30 months in 7 resected patients (all had RO resections) and 2 were 5-year survivors. This is compared to outcome in 63 patients having pelvic resection alone for recurrence: 57 % had RO resection (median OS = 36 months), 28% had R1 resection (median OS = 15 months) and 15% had R2 resection (marrow invasion) (median OS = 21 months). Conclusions: Neoadjuvant IPP may facilitate resection of advanced or (borderline resectable) recurrent rectal cancer by reducing tumor bulk and identifying therapeutic responders likely to benefit from major pelvic resection while excluding non-responders mostly likely to benefit from non-surgical therapy. The potential to induce regression and facilitate RO resection merits further exploration
The impact of perioperative red blood cell transfusion on long-term survival after hepatectomy for colorectal liver metastases.
Authors: Hallet Julie I. , Tsang Melanie , Cheng Eva , Kulyk Iryna B. , Hanna Sherif , Law Calvin , Coburn Natalie G. , Karanicolas Paul Jack
Published: February 2017

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Background: Perioperative red blood cell transfusions (RBCT) are associated with postoperative morbidity and may increase cancer recurrence through immunologic mechanisms following resection of colorectal liver metastases (CRLM). We sought to explore the relationship between RBCTs and long-term survival following resection of CRLM in the contemporary surgical era. Methods: We conducted a retrospective review of a prospective database including all patients undergoing partial hepatectomy for CRLM from 2003-2012. Data regarding date of death was abstracted from a validated, population-based cancer registry. Primary outcome was overall survival (OS), compared based on RBCT (defined as time of surgery to 30 days following surgery) and on number of RBC units received using Kaplan-Meier curves. Cox regression analysis was performed to examine the association between RBCT and OS, while adjusting for prognostic factors including Fong score and period of treatment (2003-2007 vs. 2008-2012). Results: We included 483 patients operated for CRLM, of which 27.5% received RBCT. 90-day post-operative mortality was 4.8% and median follow-up was 33 (IQR: 20.1-54.8) months. Median survival in patients who received RBCT was 44.5 months compared with 93.5 months in patients who did not(p<0.0001). The difference persisted in subgroup analysis excluding patients who died within 90 days of surgery (62.3 vs. 93.5 months, p=0.023). After adjustment for Fong score and period of treatment, RBCT was independently associated with decreased OS (HR 2.15; 95% CI: 1.52-3.04). Conclusions: Perioperative RBCT is independently associated with decreased OS following hepatectomy for CRLM. Interventions to minimize and rationalize the use of RBCT for hepatectomy are warranted in order to mitigate this detrimental effect on long-term outcomes.