bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment sequencing and outcomes in synchronous metastatic rectal cancer.
Authors: Strach Madeleine Cornelia , Lee Margaret , Lomax Anna , Ng Michael , Guerrieri Mario , Prasanna Thiru , Wong Hui-li , Lee Belinda , McKendrick Joseph James , Lim Lionel , Kosmider Suzanne , Tie Jeanne , Yip Desmond , Nott Louise M. , Johns Julie , Harold Michael , Gibbs Peter , Wong Rachel
Published: March 2017

750

Background: Optimal sequencing of therapies in synchronous metastatic rectal cancer (SMRC) remains unknown. Aim: To compare sequencing of treatment modality and outcomes in SMRC. Methods: Retrospective audit of patients with SMRC registered on the multi-centre Treatment of Recurrent and Advanced Colorectal Cancer database between 1/1/2009 and 30/6/2015. Patients were grouped according to initial treatment mode: chemotherapy (C), chemoradiation (CRT), surgery (S) and best supportive care (BSC). Results: 247 patients were identified: median age was 62yrs, ECOG 0-1 87%, male 64%, 1-2 metastatic sites 86% (liver 56%) and treatment intent was curative in 14%. Median follow-up was 19m. Primary tumour resection occurred in 95 patients (38%). Compared to no resection, these patients had improved median OS (41 vs 16 months; p < 0.0001) and PFS (15 vs 10 months; p < 0.0001). There was no difference in outcome with varying treatment combinations and sequences of S with CRT/C (p > 0.05). For unresected patients, the most common initial treatment was C (30%). Any active treatment was associated with better OS compared to BSC (6.4m): C (16.1m, p < 0.0001), CRT (20.6m, p = 0.001) and C&CRT (21.8m, p < 0.0001). Most active treatments were associated with better PFS compared to BSC (6.4m): C (10.8m, p = 0.015) and C&CRT (10.6m, p = 0.012). There was no significant PFS difference comparing BSC to CRT (p = 0.25). There were no OS nor PFS differences between: comparisons of C, CRT and C&CRT (p > 0.05). Initial treatment strategies were compared for 129 patients receiving multimodal therapy, where 22 (17%) had initial treatment with C (60% subsequent resection) compared to 85 (66%) commencing with CRT (70% subsequent resection). Commencing with CRT was associated with a longer OS compared to C (31 vs 21 months; p = 0.014). Conclusions: For patients undergoing primary tumour resection, no difference in outcomes were demonstrated with the addition of C and/or CRT. For unresected patients, there was a survival benefit associated with active therapy, with no significant difference between C, CRT or C&CRT. This supports the current practice of using these modalities at clinicians’ discretion. Review of patient factors potentially influencing treatment choice is ongoing.
High-dose neoadjuvant intensity modulated radiotherapy/chemotherapy for distal rectal cancer followed by rectal sparing TEM.
Authors: DeNittis Albert S. , Parikh Kinjal , Zeger Erik L. , Marks Gerald J. , Marks John
Published: March 2017

756

Background: In patients with distal rectal cancer, preoperative chemoradiotherapy remains the standard of care, however intensity modulated radiation therapy (IMRT) followed by trans-anal endoscopic microsurgery (TEM) may be able to provide more conformal and higher hoses of radiation while sparing normal tissue. It is our intent to present 11 years of experience of patients treated concurrently with chemotherapy and IMRT followed by rectal sparing TEM. We will report on local control, disease free survival (DFS), and toxicity. Methods: Forty-two patients at Lankenau Medical Center were treated for distal rectal carcinoma with IMRT and TEM from 2004 to 2016. Patients staged T1-T3 N0 M0 received 5580 cGy to the pelvis using a 9 field plan or volumetric arc therapy targeting rectal tumor and pelvic lymph nodes. The median age was 68. All patients received concurrent 5FU based chemotherapy; 54% received an infusional regimen and 46% received oral capecitabine. All patients went on to surgery with full thickness local excision via TEM. 38 underwent surgery within 7-12 weeks following neoadjuvant therapy, with median time to surgery at 11 weeks. Results: Median time to follow up time was 33 months. Complete pathologic response was achieved in 38% (n=17) of patients, good partial response in 53% (n=22), and moderate response in 6%. 4 patients had local recurrence all achieving long term control with salvage surgery. 5 patients developed distant metastasis, most commonly to the liver. Of those, 1 died from metastatic disease, occurring 11 years after initial diagnosis. 79% of patients are currently alive with no evidence of disease. Mean DFS calculated with Kaplan Meier analysis was 88 months with 95% confidence interval between 76 and 101 months. Toxicity was acceptable with only one grade 2 toxicity (diarrhea), and two patients with grade 1 neutropenia. Conclusions: Our 11 year patient experience has shown that neoadjuvant chemoradiotherapy with IMRT followed by TEM is an effective and well tolerated treatment regimen for distal rectal carcinoma. In the appropriately selected patients, local excision surgery may provide an excellent option for patients other than low anterior resection (LAR).
Outcomes in the second line treatment of metastatic colorectal cancer (mCRC): Findings from 6,462 patients (pts) in the ARCAD database.
Authors: Leal Alexis Diane , Ou Fang-Shu , De Gramont Aimery , Pederson Levi , Sobrero Alberto F. , Peeters Marc , Arnold Dirk , Pitot Henry C. , Rothenberg Mace L. , Giantonio Bruce J. , Van Cutsem Eric , Sargent Daniel J. , Grothey Axel
Published: March 2017

757

Background: Progression free survival (PFS) and overall survival (OS) appear to differ across trials, even when pts receive the same regimen (REG). This analysis aimed to benchmark the clinical outcomes in the 2nd line treatment of metastatic colorectal cancer (mCRC). Methods: Individual patient (pt) data was available on 6,462 pts with mCRC enrolled in 7 2ndline clinical trials (8 REGs) in the ARCAD database. Regimens used in at least two trials included FOLFIRI +/- an EGFR inhibitor (EGFRi), FOLFOX +/- a VEGF inhibitor (VEGFi), and irinotecan (IRI). Descriptive statistics were used to describe pt demographics. Multivariable Cox models were used to assess differences (DIFFs) in PFS and OS, while p-value <0.05 were considered statistically significant (SS). Results: 500-1400 pts received each REG (see Table). Median OS and PFS differed by 0.2 to 4.6 months (mo) and 0.8 to 2.5 mo across trials within the same REG. These DIFFs were SS except for PFS in REGs containing FOLFIRI +/- EGFRi. After multivariable adjustment, all DIFFs in OS were attenuated and non-significant. DIFFs in PFS attenuated for most REGs but remained SS for FOLFOX and IRI. Conclusions: After multivariable adjustment, there were no SS DIFFs in outcomes across trials within the same REG, with the exception of PFS in FOLFOX and IRI. The initial observed DIFFs in outcomes could be due to confounding factors and the remaining SS DIFFs in PFS in FOLFOX and IRI may be due to variation in definition of progression across trials. Therefore, caution is warranted when using historical data to design future trials.[Table: see text]
Effect of arsenic trioxide on epithelial-mesenchymal transition via induction of SH2?containing protein tyrosine phosphatase 1.
Authors: Park Jong-Jae , Joo Moon Kyung , Yoo Hyo Soon , Lee Beom Jae , Kim Taehyun , Lee Ji ae , Sim Yu-ra , Choi Wonjae , Chun Hoon Jai , Lee Sang Woo , Bak Young-Tae
Published: March 2017

76

Background: Arsenic trioxide (ATO) is known to inhibit epithelial-mesenchymal transition (EMT) in hepatolocellular carcinoma and breast cancer cells, however, little has been reported in gastric cancer cells. In this study, we aimed to investigate the mechanism of ATO to inhibit signal transducer and activator of transcription 3 (STAT3) activity and EMT in gastric cancer cells. Methods: We performed wound closure assay and Matrigel invasion assay for functional studies of EMT, and western blot for measurement of protein markers using AGS gastric cancer cells. Results: Compared with control, 5 and 10 μM of ATO significantly inhibited cellular migration and inhibition in a dose-dependent manner. Furthermore, ATO significantly downregulated snail expression, a mesenchymal marker, and upregulated E-cadherin expression, an epithelial marker. We could observe that ATO induced SH2-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor type protein tyrosine phosphatase, and subsequently downregulated phospho-STAT3 in a dose-dependent manner. To validate the molecular link between ATO and SHP1 to inhibit EMT in gastric cancer cell, we pre-treated 50 μM of pervanadate, a phosphatase inhibitor, before treatment of 10 μM ATO, and this significantly abolished anti-invasive effect by ATO in AGS cells. In xenograft tumor model, intraperitoneal injection of ATO significantly reduced the tumor volume and upregulated SHP-1 expression by immunohistochemistry stain compared with vehicle, which were reversed by ATO with pervanadate injection. Conclusions: Our findings suggest that ATO may show anti-EMT effects via induction of SHP1 and inhibition of STAT3 activity in gastric cancer cells.
An update on rectal cancer evaluation by magnetic resonance imaging in neoadjuvant therapy decision making: Retrospective case review.
Authors: Recio Boiles Alejandro , Howell Krisha , Kalb Bobby T. , Malangone Steve , Nfonsam Valentine N. , Elquza Emad
Published: March 2017

762

Background: During the last decade, MRI used for staging of rectal cancer has been reported to up or down stage rectal cancer by 20%. Poor staging affects guided pre-operative decision-making. Adequate staging would enable to stratify treatment, avoiding unnecessary surgical morbidity and allowing aggressive interventions according to patient risk. After novel techniques and image acquisition for MRI became available at our Cancer Center, we aimed to analyze perfusion pattern and qualitative T2 signal before and after chemoradiationtherapy (CRT) tumor response to the gold standard pathological stage. Methods: Data was retrospectively reviewed from our institution cancer registry. Patients were selected with a diagnosis of rectal cancer by biopsy, between 2011-2015. Inclusion criteria were to have documented radiological AJCC 7th edition < IV, accessible diffusion weighted MRI for apparent diffusion coefficient analyzes, completed CRT and pathology report. Results: A total of 57 patients were diagnosed with rectal cancer during this time period, of which 20 fulfilled inclusion criteria; median 61 years old, 80% males, stage IIA (6) IIIB (10) and IIIC (4), LAR 60% and APR 40%. After CRT, 90% of patients (N18) were downstaged (and 2 upstaged) on pathological review. 10 patients had a repeat pre-operative MRI. Post-treatment MRI re-stage correlated with surgical pathological stage in all 10 patients (Table). 4 patients received unnecessary APR and 2 may had benefit from further CRT or total pelvic exanteration. Conclusions: In retrospective, tumor response evaluation post CRT with high-resolution MRI correlated with pathological stage. Our analysis pointed 20% patients may avoid a morbid surgery while 10% would have required more aggressive therapy. Future clinical decisions will be complemented by repeat MRI analysis aiding surgical and clinical decision-making. [Table: see text]
Patient reported distress is predictive of survival in patients with gastrointestinal tumors.
Authors: Whitaker Dale Alan , Hintenlang Lauren L. , Jagadsh Niveditha , Strong Gerald , Buskirk Steven J. , Peterson Jennifer Layton , Tzou Katherine S. , Ko Stephen , Vallow Laura , May Byron C. , Habboush Jacob , Hollant Laeticia , Miller Robert Clell
Published: March 2017

764

Background: Psychosocial distress screening and assessment in patients with gastrointestinal (GI) cancers has an established importance due to the distress experienced during and post treatment. GI cancer patients receiving radiotherapy (RT) for curative or palliative measures were reviewed in order to determine if there was a relationship between patient reported distress (PRD) and survival. Methods: Patients at our institution who receive external beam RT for GI cancers completed a 30 question PRD survey that also included a linear analog measure of overall distress, the National Comprehensive Cancer Network (NCCN) Distress Thermometer, which ranged from 1 (low overall distress) to 10 (high overall stress) at the start of and/or during treatment. Each question on the PRD questionnaire concentrated on a possible cause of distress. It allowed patients to rate distress levels for each question from 1 to 5 (1 being the least distressed and 5 being the most distressed), and also overall distress according. The reported clinical results of the PRD questionnaire were retrospectively reviewed in patients receiving RT for GI cancers from Jan 2012 to Aug 2015. Patients were considered distressed if their overall PRD score was 5 or greater (PRD+) or not distressed (PRD-) if their score was 4 or under. Overall survival between PRD+ and PRD- was compared using the Kaplan-Meier method. Results: PRD surveys were completed by 134 consecutive patients, 67 (50%) male and 67 (50%) female within 30 days of starting RT. The median age was 65 years (range 28 to 93). The top histological finding was adenocarcinoma, 90 patients (60%). 113 (84%) received chemotherapy and 64 (48%) underwent surgery. 102 (75%) treatments were curative and 32 (25%) were palliative. Overall NCCN distress thermometer results ranged from 0 to 10, with a median of 4. Median follow-up was 2.7 years. Distressed patients (PRD+) had inferior survival to those not distressed (PRD-) at 2 years, 52% vs. 72%, p<0.02. Conclusions: Patient reported distress is associated with an inferior survival in patients receiving radiotherapy for gastrointestinal tumors.
Effect of extended postoperative recovery on long-term oncological outcomes.
Authors: Poli Elizabeth , Sekigami Yurie , Rajeev Rahul , Gamblin T. Clark , Turaga Kiran
Published: March 2017

765

Background: Curative cancer surgery remains the cornerstone of treatment of localized malignancies. Extended post operative recovery (eLOS) is associated with debility and immunosuppression. We hypothesized that eLOS is associated with worse long term oncological outcome. Methods: The NCDB participant user file from 2004-13 was utilized to identify patients with localized gastrointestinal malignancies undergoing curative cancer resections. Quartiles (Qx) of length of stay (LOS) were calculated based on histology and site specific indicators. Survival modeling was performed using cox-proportional hazards and conditional models were created. Alpha of 0.05 was set for statistical significance. Results: Of 1,616,215 patients in the cohort, 577,860 patients were included who met inclusion criteria. Majority of patients were ≥65 years (56%) with a predominance of colon cancer (70%). The median length of stay (LOS) varied from 5 days (partial hepatectomy) to 10 days (esophagectomy). After adjusting for age, gender, stage, and site of disease, increasing length of stay was significantly associated with worse oncological survival with a dose response effect (Q1 HR 1.0, Q2 1.12 (1.10-1.14) p<0.001, Q3 1.42 (1.41-1.44) p<0.001 and Q4 1.82(1.80-1.85), p<0.001). Conditional overall survival for patients who survived 3, 6 and 12 months after surgery, was worse with eLOS (p<0.001). Conclusions: Longer than expected length of stay after an index curative cancer operation leads to worse overall oncological outcomes. This effect persists even after excluding patients who suffer delayed post-operative mortality within 12 months after the operation. More research needs to be done to determine if this outcome is related to perioperative immunosuppression.
Rapid characterization of candidate loss of function genes in primary organoid culture.
Authors: Hart Daniel James , Salahudeen Ameen Abdulla , de la O Sean , Han Kyuho , Morgens David , Bassik Michael , Kuo Calvin Jay
Published: March 2017

77

Background: Genome scale sequencing efforts have identified chromosomal deletions and non-synonymous mutations as putative drivers of gastro-intestinal cancer. There is a need to rapidly validate these drivers in robust models. The culture of primary, non-transformed tissues in vitro as three-dimensional organoids that accurately recapitulate organ structure and physiology serves as an ideal model for such validation, and many other applications in biology. Methods: Mouse wild type and p53 flox/flox upper digestive tract tissue containing epithelial and mesenchymal components were cultured in an air-liquid interface and subjected to adenovirus expressing either a functional control or Cre recombinase. Resultant organoids were passaged at confluency until dysplasia was evident in histology. A lentiviral shRNA (loss-of-function) screen was then conducted, where proliferative activity was measured with barcode reads from the pooled library. Results: p53-null organoids showed histology consistent with human gastrointestinal cancer. These organoids were also able to form small tumors when injected subcutaneously into immune-deficient mice. The pooled lentiviral shRNA screen functionally validated candidate drivers. Conclusions: Gastrointestinal organoids are a suitable model for the introduction of oncogenic mutations in a tractable and replicable format. In future work we will validate loss-of function and gain-of-function screens with CRISPRi/a libraries, and replicate these screens in human gastrointestinal organoids.
Left versus right: Does location matter for refractory metastatic colorectal cancer (mCRC) patients in phase I clinical trials?
Authors: Patel Sukeshi R. , Ketchum Norma S. , Michalek Joel , Gelfond Jonathan , Mahalingam Devalingam
Published: March 2017

771

Background: Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) vs EGFR-I given first-line to mCRC patients (pts) (ASCO 2016). However, little is known regarding the effect of location on prognosis and prediction in heavily pretreated mCRC pts. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in pts with refractory mCRC enrolled in early phase studies. Methods: A historical cohort analysis of mCRC pts enrolled amongst 44 phase I trials at the IDD from 3/2004 - 9/2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: 139 pts, median age 59 (33-81), KRAS mut 20 %, wt 31 %, unknown 49 %. ≥ 3 prior lines therapy 73.9 %; Prior EGFR-I 75.5% (100% of KRAS wt). Location: Right 20.9 %, Left 61.9 %, Transverse 4.3 %, Unknown 12.9 %. Phase I agents: VEGF I 19.4%, EGFR/Growth Factor I 9.3%. For survival analysis, transverse were included with right. Of 112 pts, mOS: Left (n = 80) 6.6 months (mo) vs Right (n = 32) 5.9 mo, p = 0.18. mPFS: Left (n = 86) 2.0 mo vs Right (n = 35) 2.0 mo, p = 0.76. Survival in regards to location or biologic agent (table). Conclusions: In phase 1 clinical trials, although location alone was not prognostic in heavily pretreated pts, left-sided mCRC had improved survival with EGFR-I. Despite progression on EGFR I, left-sided KRAS wild mCRC pts should be considered for phase 1 studies of agents targeting the growth factor pathways. [Table: see text]
Impact of RAS testing on treatment duration among patients with metastatic colorectal cancer (mCRC).
Authors: Bach Bruce A. , Christodoulopoulou Alexandra , Klink Andrew , Hechmati Guy , Mujumdar Urvi , Feinberg Bruce A. , Fakih Marwan
Published: March 2017

773

Background: Current clinical guidelines recommend that all patients with mCRC have tumor tissue genotyped for RAS mutations. Tumor RAS testing enables the widest range of treatment options, with potential impact on patient outcomes. The aim of this study was to estimate the impact of RAS testing on the duration of treatment, across multiple lines of chemotherapy in mCRC. Methods: Adults with a diagnosis of mCRC (ICD-9 codes 153.x, 154.0x, or 154.1x and 197.x–198.x) were identified from a database of US public and private insurance claims (129 million covered lives) from 2012–2014. Time to treatment discontinuation, overall and by line of chemotherapy, was compared through univariate analysis between patients who were tested for RAS mutations (identified by CPT codes) to those who were not tested. Multivariate Cox proportional hazard regression model was used to estimate the risk of discontinuation attributable to prior RAS testing (i.e., hazard ratio [HR]), adjusting for patient characteristics. Results: We identified 4,527 mCRC patients (mean age at diagnosis, 61.2 years; 54% male), 39% (n = 1,787) of whom had a claim for RAS testing during the study period. Patients tested for RAS mutations stayed on treatment significantly longer in first-line (1LD), second-line (2LD), and overall treatment (OTD) vs those who were not tested for RAS mutations (1LD: median, 245 days [95% confidence interval–CI: 232–251] vs 196 days [95% CI: 189–205]; 2LD: median, 189 days [95% CI: 168–203] vs 147 days [95% CI: 133–161]; OTD: median, 903 days [95% CI: 815–1,040] vs 305 days [95% CI: 281–337]; all P < 0.01). Adjusting for patient characteristics, RAS testing significantly reduced the risk of discontinuation in 1LD, 2LD, and OTD (HRs: 0.83 [95% CI: 0.76–0.90], 0.80 [95% CI: 0.71–0.91], and 0.32 [95% CI: 0.27–0.37], respectively; all P< 0.01). Conclusions: These observational data show that RAS testing is associated with significantly greater time on treatment for mCRC patients compared to not testing, suggesting that patients under the care of physicians who decide to test for RAS mutations, regardless of test result, are on therapy for a longer period of time than untested patients.
Analysis of clinical and research implications of expanding next-generation sequencing (NGS) libraries in the treatment options of gastrointestinal cancers in a large cancer center.
Authors: Gonzalez Velez Miguel , Duma Narjust , Jaramillo Restrepo Valentina , Lopez-Zertuche Pablo , Kothadia Sejal , Mariotti Veronica , Parrondo Ricardo Daniel , Boseski Beth , Jennis Andrew , Gutierrez Martin
Published: March 2017

774

Background: The use of next-generation sequencing (NGS) in clinical practice has increased the therapeutic options for many cancers. Multiple NGS assays are now commercially used. The genomic libraries used by these assays are continuously being expanded, resulting in increased detections of genomic alterations (GAs) leading to potential new treatments. The aim of this study was to identify the clinical and research implications of a database expansion in the detection of GAs in patients with gastrointestinal cancers (GIC). Methods: We retrospectively analyzed 83 consecutive patients with GIC that had NGS at the John Theurer Cancer Center between 01/2014 and 08/2016. GAs were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA). GAs, number of genomic-directed therapies and number of clinical trials were reviewed. Results: Period 1 (P1) comprised 01/2014-09/2014, period 2 (P2) comprised 10/2014-08/2016. The NGS assay interrogated 236 genes and introns of 19 genes during P1, and was expanded to 315 genes and introns of 28 genes during P2. The 21 samples analyzed during P1 harbored a total of 82 GAs with an average of 3.9 GAs/sample (range 1-7). The 62 samples analyzed during P2 harbored a total of 342 GAs with an average of 5.5 GAs/sample (range 1-20); representing an increase of 42% in GAs from P1 to P2. 41 GAs in 29 genes were detected in P2 that were not interrogated during P1. The average of genomic-directed therapies with potential clinical benefit increased from 1.8 during P1 vs 2.6 during P2 (44.4% increase in potential therapies). Based on new genomic findings, more clinical trials were made available during P2; an average of 8 vs 4 clinical trials (100% increase in available clinical trials). Conclusions: Periodical updates on NGS and the expansion of genomic libraries increase the detection of GAs, potential new genomic-directed therapies and available clinical trials. Continued expansions of NGS are needed to improve genomic characterization, and increase in the personalized therapeutic options for our patients with GIC.
Effect of subsequent chemotherapy on overall survival in first-line chemotherapy with targeted agents for patients with metastatic colorectal cancer: Systematic review and meta-analysis of randomized control trials.
Authors: Sakai Daisuke , Kudo Toshihiro , Kato Aya , Sueda Toshinori , Takahashi Hidekazu , Haraguchi Naotsugu , Nishimura Junichi , Hata Taishi , Matsuda Chu , Mizushima Tsunekazu , Doki Yuichiro , Mori Masaki , Satoh Taroh
Published: March 2017

782

Background: One of recent standard first line chemotherapies for metastatic colorectal cancer is doublet of cytotoxic agents, fluorouracil and oxaliplatin or irinotecan, in combination with target agent, bevacizumab, or anti-EGFR antibody as cetuximab or panitumumab for KRAS or RAS wild type (WT). In this decade, nevertheless progression free survival (PFS) of clinical trials was little improved, overall survival (OS) had been increased. Methods: We analyzed data from 14 recently published phase III randomized clinical trials in mCRC to correlate the percentage of patients receiving subsequent chemotherapy with the reported OS. Results: Median PFS and OS were 10.3 and 25.0 months, respectively. In all comer trials, median OS is significantly correlated with the percentage of patients who received subsequent chemotherapy after first line chemotherapy of their disease [regression coefficient (R2) = 0.85 p = 0.0018]. In trials with KRAS WT, a correlation between OS and the rate of subsequent therapy was modest [r2 = 0.605, p = 0.0637]. Median PFS and RR were not correlated with median OS. Conclusions: Our results support the strategy of making salvage chemotherapy available to all patients with advanced CRC to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, PFS might no longer be regarded as the appropriate surrogate end point of OS by which to assess the efficacy of a palliative first-line treatment in CRC.
Self-reported adherence to regorafenib for metastatic colorectal cancer: A retrospective cohort study.
Authors: Kawakami Kazuyoshi , Suenaga Mitsukuni , Soejima Azusa , Sugita Kazuo , Yokokawa Takashi , Suzuki Kenichi , Inoue Ayaka , Machida Yohiaki , Wakatsuki Takeru , Yamaguchi Kensei , Hama Toshihiro
Published: March 2017

783

Background: Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) and it is frequently involved in various adverse events. The clinical factors affecting adherence to regorafenib remain unclear. The aim of this study is to evaluate adherence to regorafenib in patients with mCRC and to identify candidate factors which might have influence on adherence to regorafenib. Methods: We evaluated 106 consecutively enrolled patients with mCRC who received regorafenib between May 18, 2013 and March 2, 2015 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Adherence to regorafenib was checked by pharmacists using a self-reported treatment diary for patients at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of actual intakes per 21 intakes scheduled in each cycle. We retrospectively surveyed median relative dose intensities of regorafenib and the factors deteriorating adherence across three cycles. Univariate analyses were then performed using patient socio-demographic factors and clinical factor. Multivariate analysis was performed using logistic regression. Significance levels for uni- and multivariate analyses were p < 0.2 and p< 0.05, respectively. Results: A total of 81 patients were evaluated in the study analysis. Adherence rates were 64.4% in the first cycle of regorafenib treatment, 77.4% in the second cycle, and 83.8% in the third cycle. The median relative dose intensity was 57.6%. The most common reasons for non-adherence were hand-foot skin reaction (34.3%, 331 instances), and liver dysfunction (15.3%, 148 instances). In multivariate analysis, increased non-adherence to regorafenib was significantly associated with gender (female) [odds ratio (OR) = 0.20; 95% confidence interval (CI): 0.06-0.68, p = 0.01] and adverse events ( ≥ Grade 3) [OR = 3.16; 95% CI: 1.00-9.97, p= 0.04) in the first cycle.] Conclusions: The high frequency of treatment-related hand-foot skin reaction and liver dysfunction is the main factor affecting adherence to regorafenib. Intensive supportive care in the management of these symptoms could assist adequate adherence to regorafenib.
Adjuvant treatment in extreme elderly patients with colorectal cancer.
Authors: Llopis Cuquerella Marta , Ors Castaño Maria del Carmen , Ballester Espinosa María , Magdaleno Cremades Alejandra , Boix Aracil Vicente , Ramirez Belloch María del Rocío , Morales Giménez Roberto , Gómez González Lucía , Asensio Martinez Elena , Navalón Coronado Juan Carlos , Navarro Rodriguez Jose Manuel , Soliveres Soliveres Edelmira , Morcillo Ródenas Miguel Ángel , Gallego Plazas Javier
Published: March 2017

784

Background: Surgical and adjuvant treatment in extreme elderly ( > 80 years) patients with localized colorectal cancer is an unresolved issue. Owing to the lack of available neither clinical practice nor investigational data in this field we present our experience in this scenario. Methods: We retrospectively reviewed data regarding surgical and complementary treatment for colorectal cancer patients aged more than 80 consecutively attended by General Surgery Department in Vega Baja Hospital between 2008 and 2013. Results: A total number of 115 colorectal cancer patients were registered. 95 patients diagnosed of localized disease were selected for analysis. Colon vs rectal cancer ratio was 4:1. Median age was 83.6 years (80-94). Male sex was predominant (60 patients, 63.2%). Emergency surgery was performed in 15 patients (15.8%). Complementary treatment to surgery was advised, according to international guidelines, in 53 patients (55.8%). 10 patients (18.9%) with an advise of adjuvant treatment finally received it. More patients with rectal cancer received recommended treatment (41.7% rectal vs 12.2% colon cancer). Patients with stage III disease were more frequently finally treated according to guidelines (22.2 % stage III vs 11.8% stage II). More patients with stage II rectal cancer were advised and received treatment (recommendation: 66.7% rectal vs 36.1% colon cancer; administration: 25% rectal vs 7.7% colon cancer). Treatment was also more frequently administered to stage III rectal cancer (50% rectal vs 14.3% rectal cancer) (Table). Conclusions: Our experience in localized colorectal cancer in extreme elderly patients ( > 80 years) showed that, although advised according to guidelines, most of them did not receive adjuvant treatment to surgery. Complementary treatment administration was more common in rectal cancer patients and with more advanced disease. [Table: see text]
Prognostic impact of tumor (T) and lymph node (N) status in metastatic colon cancer (MCC): A validation study using the National Cancer Database (NCDB).
Authors: Mukkamalla Shiva Kumar Reddy , Somasundar Ponnandai Sadasivan , Rathore Bharti
Published: March 2017

786

Background: T and N status are not routinely utilized in prognosis of MCC. We had previously demonstrated that T and N serve as independent predictors for overall survival (OS) in MCC using SEER [Ann Oncol (2014) 25 (suppl 4): iv172-iv173]. The current study is undertaken to validate our findings using the NCDB. Methods: The NCDB was queried for patients diagnosed with MCC from 2004-2008 with survival information up to 2013. Pearson Chi-square test, Kaplan Meier survival curves and Cox proportional hazards model were used for statistical analysis. Results: A cohort of 5,788 patients was identified for analysis. Frequencies of T1, T2, T3 and T4 among the study population were 6.6%, 4.2%, 52.6% and 36.6% respectively, whereas N0, N1 and N2 were noted in 28.5%, 29.9% and 41.6% respectively. 5-year OS worsened with advancing T and N status, with the exception of T1 disease (Table). T1 disease was associated with poor prognosis compared to T2 and T3, but showed better survival outcome than T4 (p < 0.05). Both T and N were identified as independent predictors of OS regardless of age, gender, race, comorbidity index, insurance status, income level, tumor sidedness, tumor grade, surgery, chemotherapy and academic level of treating institution. In multivariate analysis, we found left sided tumors to have better survival outcome compared to right (HR 0.85; p < 0.0001). Conclusions: Similar to our previous findings, in MCC patients, a T1 status portends poor prognosis compared to T2 or T3 disease. It is possible that an overrepresentation of tumors, with a distinct biological subtype characterized by a tendency for early dissemination in T1 disease could be associated with poor outcomes observed in this patient subgroup. In future, we plan to validate this finding through T1 subgroup analysis. Our study also demonstrates poor OS in right sided tumors compared to left sided tumors, similar to prior studies by Schrag et al and Venook et al. [Table: see text]
Impact of robotic-assisted approach on lymphadenectomy for colorectal cancer.
Authors: Gamagami Reza , Kozak Paul , Kakarla Venkata R.
Published: March 2017

787

Background: In most recent years, robotic assisted laparoscopic surgery (RALS) has proven to be a viable alternative to laparoscopic and traditional open surgery for colorectal cancer. Obtaining the adequate number of lymph nodes is not only essential for accurate staging, but also impacts both prognosis and the need for adjuvant chemotherapy. To date, the efficacy of lymph node harvest for RALS is not well studied or established. The aim of our study is to analyze the impact of RALS on lymphadenectomy for colorectal cancer. Methods: We performed a retrospective review of patients who underwent curative resections for colorectal cancer over a five-year period at a single institution by a single surgeon. Resections were classified as right-sided, sigmoid, or rectal, and subdivided into robotic and non-robotic surgery groups. The demographic data and histopathology were obtained, with an emphasis on the number lymph nodes harvested (LNH) during resections. Emergencies and non-curative resections were excluded. Results: Between January 2010 and December 2015, 136 patients with colorectal cancer underwent curative resections. Sixty-four underwent right-sided resections (28 laparoscopic, 36 robotic). Twenty-five underwent sigmoid resections (11 laparoscopic, 14 robotic), and 47 underwent rectal resections (15 open, 32 robotic). There was no significant difference in age, sex, BMI and ASA scores between the cohorts examined. The mean number of LNH with RALS was significantly higher in all three groups (right-sided—24 vs. 15 ( p= .0001), sigmoid—16 vs. 12 ( p= .046), rectal—19 vs. 4 ( p= .0016)). There was no difference in the rate of adequate lymph node extraction for staging purpose, i.e., 12 lymph nodes in all three groups. Conclusions: Robotic-assisted laparoscopic surgery is associated with a statistically significant increase in lymph node harvest for right-sided, sigmoid and rectal resections for malignancy. Future studies with larger sample sizes are necessary to validate these findings.
Comorbidities limiting recruitment of colorectal cancer (CRC) patients in early-phase trials.
Authors: Duma Narjust , Wang Yucai , Gonzalez Velez Miguel , Kothadia Sejal , Mariotti Veronica , Parrondo Ricardo Daniel , Hubbard Joleen Marie , Adjei Alex A. , Halfdanarson Thorvardur Ragnar
Published: March 2017

791

Background: With the surge of drug development in the past decade, early phase clinical trials (EPCT) have gained value evaluating the potential benefits of new therapies. The inclusion/exclusion criteria in EPCT are usually rigorous and may exclude many patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for CRC. Methods: ClinicalTrials.gov was queried on December 1stof 2015. We reviewed the characteristics and eligibility criteria of 369 phase I/II interventional drug trials including: experimental arm therapy, location, and exclusion/inclusion criteria. Logistic regressions were completed and exclusion was studied as a binary variable. Results: Of the 369 trials, 68% were phase II and 32% phase I. 46% were conducted in the United States, 30% in Europe, 15% in Asia and 9% in other locations. 74 (20%) trials excluded pts > 70 years of age. 142 (39%) trials required creatinine levels < 1.5 mg/dl, liver enzymes (AST/ALT) < 2.5 and bilirubin < 1.5 of the upper limit of normal. Cytopenia was a significant exclusion factor: 147 (47%) trials required Hgb > 9 g/dl and 218 (59%) excluded pts with platelets < 100,000/dl. In terms of comorbidities, 98 (27%) trials excluded pts with heart failure (NYHA class 3/4), 74 (20%) with atrial fibrillation, 112 (31%) with any anticoagulation therapy and 155 (42%) with positive HIV. Trials located in the US were more likely to exclude pts with Hgb < 9g/dl (OR: 1.5, 95%CI: 1.1-2.3, p < 0.05), immunotherapy trials were more likely to exclude pts on any anticoagulation (OR:1.8, 95%CI: 1.2-2.8, p < 0.007) and targeted therapy trials were more likely to exclude pts with history of DVT/PE or cardiovascular diseases (OR: 3.4, 95%CI: 1.9-5.8, p < 0.0001; OR: 2.3, 95%CI: 1.3-3.8, p < 0.002, respectively). Conclusions: 20% of EPCTs on CRC excluded pts with advanced age, organ dysfunction and common comorbidities. Many of the EPCT reviewed were not inclusive of our aging oncology population who are more likely to have multiple comorbidities. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols.
Pembroliuzmab in gastrointestinal (GI) malignancies with defective DNA mismatch repair (dMMR): A single institution experience.
Authors: Cavalieri Courtney C , Swanson Eric , Whisenant Jonathan R. , Weis John R. , Gilcrease Glynn Weldon , Stenehjem David D. , Sharma Sunil , Garrido-Laguna Ignacio
Published: March 2017

792

Background: Defective DNA mismatch repair is associated with increased mutation load and expression of neoantigens. Increased activity of PD-1 inhibitor is reported in patients with GI cancers with dMMR. Here, we describe our experience at Huntsman Cancer Institute with PD-1 inhibition in subjects with GI malignancies with dMMR. Methods: Retrospective chart review of patients with metastatic GI malignancies with dMMR, treated with pembrolizumab at Huntsman Cancer Institute between July 15, 2015 and September 26, 2016. Results: A total of 9 patients were identified that received at least 1 dose of pembrolizumab (colorectal n=5; cholangiocarcinoma n=2; pancreatic n=2). Of the 9 patients, 5 received concurrent cytoxic chemotherapy. Median number of doses given was 3 (range 1 to 17). Three patients received pembrolizumab on clinical trial with concomitant mFOLFOX6. Five patients have restaging scans at the time of abstract submission. The first patient has cholangiocarcinoma and experienced a -73% response per RECIST criteria from baseline (time to progression +8 months). The second patient has pancreatic adenocarcinoma and showed a total -56.7% response per RECIST criteria from baseline (time to progression +5 months). The third patient has colorectal carcinoma and had stable disease by RECIST at restaging after 2 months (biochemical response with a 50% decrease in CEA). The fourth patient has cholangiocarcinoma and had a biochemical response with a 50% decrease in CA 19-9 and a mixed response on first restaging scan (time to progression +3.5 months). All 4 of these patients continue to have response to therapy at the time of abstract submission. The fifth patient who had colorectal cancer and died from upper GI bleeding. Restaging CT scans showed response to therapy after 6 weeks of treatment. Four additional patients initiated treatment recently and have yet to undergo restaging scans. Conclusions: Single-institution data seem to confirm activity of PD-1 inhibitor in GI malignancies that harbor dMMR. All 5 restaged patients demonstrated response to PD-1 inhibition by RECIST criteria or decreased tumor marker. Updated responses for all patients will be presented during the meeting.
Protective effect of ursodeoxycholic acid against chemotherapy-induced mucositis.
Authors: Kim Seung Han , Chun Hoon Jai , Lee Jung Min , Lee Sang Yup , Choi Byeong Kwang , Yoo In Kyung , Lee Jae Min , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Kim Chang Duck
Published: March 2017

796

Background: Gastrointestinal mucositis is a serious side effect of chemotherapy. It increases the frequency of infection, risk of bleeding, and duration of hospitalization, consequently reducing subsequent chemotherapy doses. Ursodeoxycholic acid (UDCA), which is currently used in various liver diseases, exerts direct cytoprotective effects by stabilizing membranes, inhibiting apoptosis, and acting as an antioxidant. The protective effect of UDCA against chemotherapy-induced mucositis was assessed using an in vivo animal model. Methods: Sprague-Dawley rats were randomly assigned to the following 5 groups: non-chemotherapy and vehicle; 5-fluorouracil (5-FU) and vehicle; 5-FU and 10 mg/kg/day UDCA; 5-FU and 100 mg/kg/day UDCA; and 5-FU and 500 mg/kg/day UDCA. 5-FU (400 mg/kg) or physiological saline (control) was administered by intraperitoneal injection. UDCA was orally administered 1 day before 5-FU injection for 6 days. One day after the final UDCA dose, rats were sacrificed, and the intestines were dissected for tissue sampling and laboratory analysis. Results: UDCA promoted a higher body weight recovery, decreased villus destruction, and reduced inflammatory cytokines levels, at doses of 10 and 100 mg/kg/day. Villous fusion and destruction were pronounced in the 5-FU group compared with those observed in the UDCA-treated group or controls. The jejunal villous lengths were as follows: 212.8±58.0 µm, 331.3±18.0 µm, and 310.0±112.6 µm, in the 5-FU and vehicle, 5-FU and 10 mg/kg UDCA (p = 0.006), and 5-FU and 100 mg/kg UDCA groups (p = 0.046), respectively. Real-time polymerase chain reaction (RT-PCR) showed that IL-6 and TNF-α levels decreased in the 10 mg/kg and 100 mg/kg UDCA co-administration groups. Further, myeloperoxidase activity decreased in the UDCA co-administration group. Conclusions: UDCA significantly attenuated the reduction of the height of small intestinal villi and reduced inflammatory cytokine levels, thus highlighting the potential of UDCA as a preventive agent against chemotherapy-induced gastrointestinal mucositis. The specific protective mechanisms of UDCA on the gastrointestinal tract should be determined.
Retrospective review of outcomes in patients (pts) with synchronous metastatic rectal cancer (mRC) receiving initial non-surgical management.
Authors: Torti Ella , Park James O , Chiorean E. Gabriela , Kim Edward Y. , Cohen Stacey , Coveler Andrew L.
Published: March 2017

797

Background: Management of mRC trends toward initial non-surgical management of the primary tumor based on studies demonstrating low complications rates from un-resected primary colonic tumors. The fixed location of the rectum may increase local complications. This study characterizes complications of pts with synchronous mRC with an intact primary tumor. Methods: A retrospective review of records from 2001 to 2013 identified pts with mRC by ICD-9/10 codes. Pts with treatment-naïve mRC without significant local symptomatology were evaluated. Time to complications and death were calculated. Pathology, stage, baseline CEA, RAS, BRAF and initial treatment were evaluated for prognostic significance. Results: Forty-four pts were identified with mRC; eight were excluded for initial resection for a symptomatic primary. Among the 36 evaluable pts treated with initial chemotherapy, 14 (39%) developed complications related to the primary tumor, of whom 5 (14%) developed two or more complications. Six (17%) required operative intervention due to primary tumor complications (two died prior to planned procedure). Complications were: perforations/abscesses/fistulae (6), bowel obstruction (5), severe bleeding (5), urinary obstruction/infection (3) and, pain requiring palliative treatment (1). Interventions included blood transfusions (5), stents (3), radiotherapy (3), I&D/drains (3) and, nephrostomy (2). Of 22 pts who did not develop any complications, 15 underwent curative resection of all sites of disease. Six remain disease free and nine relapsed, all distantly. None of the 14 who developed complications underwent curative operation. The median time to complication was 2.5 months. Median overall survival was 37 and 52 months for those with and without complications, respectively. Median time from complication to death was 21 months. Pts aged > 50 vs < 50 were more likely to have complications of the primary tumor (57% vs 21%). Conclusions: mRC pts with intact primary tumors may develop complications at a higher rate (39%) than those with colon cancer (11%). These findings will need to be confirmed with larger datasets and examine for specific treatment effects.
Comprehensive genomic profiling (CGP) of esophageal and tubular GI tumors to identify frequencies of ErbB family member amplification with therapeutic implications.
Authors: Bailey Mark , Ali Siraj Mahamed , Schrock Alexa Betzig , Klempner Samuel Jacob , George Ben , Lipson Doron , He Jie , Miller Vincent A. , Stephens Phil , Ross Jeffrey S.
Published: March 2017

8

Background: As described in the MyPathway study, amplification and other mutations in ErbB-family proteins are actionable events across solid tumors. Targeting ERBB2 amplifications (amp) in tubular GI cancers (TGC) improves patient outcomes. ErbB family comparisons across anatomic sites is lacking and here we describe the largest known series in TGC. Methods: DNA was extracted from 12,685 FFPE clinical TGC specimens, including 1,720 esophageal CA*. CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of 720X for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: Across all TGC cases, amp was the most frequent genomic alteration among ErbB members at 8.7%. ERBB2 amp was 2.3x as common as EGFR amp across TGC. Across TGC sites, EGFR amp was most frequent in esophageal SCC (13.7%) and ERBB2 amp was most common in gastroesophageal junction adenoCA (21%) compared with overall frequencies of 2.7% and 5.5% respectively. ERBB3 and ERBB4 amp were rare, and most common in gastroesophageal adenoCA relative to other TGC. Clinical support with outcomes for patients treated with anti-ErbB targeted therapy across TGC will be presented, including profiling from cases of acquired resistance to anti-ErbB targeted therapy. Conclusions: Among TGC, esophageal CA harbored the most ErbB family member amp with variation by histology. Profiling across ErbB proteins in TGC suggests biologic differences and may affect response to treatment. CGP can expand the population who may benefit from anti-ErbB directed therapies and refine treatment choices. Further research is warranted. [Table: see text]