bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-course evaluation of survival and treatment in FIRE-3 (AIO KRK0306, first-line therapy of KRAS wild-type metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab).
Authors: Modest Dominik Paul , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Sobrero Alberto F. , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Seipelt Gernot , Lerchenmuller Christian A. , Kahl Christoph , Kullmann Frank , Stauch Martina , Scheithauer Werner , Held Swantje , Moehler Markus H. , Jung Andreas , Kirchner Thomas , Heinemann Volker
Published: February 2017

617

Background: FIRE-3 reported overall survival (OS) difference in favour of arm A (FOLFIRI plus cetuximab, N= 297 pts.) compared to arm B (FOLFIRI plus bevacizumab, N= 295 pts.) in the absence of significant differences in progression-free survival and response rate. Methods: We subdivided the study into six-month time intervals, starting at the time point of randomisation and evaluated OS in a time-wise fashion. Within each interval, OS was analyzed by Cox regression. Furthermore, systemic treatment and local interventions were investigated in the respective time-frames. Results: The time-course hazard ratios of OS are summarized in the Table. Pronounced differences in overall survival by time-interval analysis are observed between 24 and 30 months and between 30 and 36 months. Within the interval of 24-30 months, 24.6% (73/297) of pts in arm A and 25.1% (74/295) of pts in arm B received systemic therapy (any treatment-line). In the subsequent interval of 30-36 months, systemic anti-tumor treatment decreased to 18.9% (56/297) of pts in arm A and 16.3% (48/295) of pts in arm B. Median time on treatment was less than 2 months in the intervals of 24-30 months and 30-36 months. Updated data including RAS wild-type population will be presented at the meeting. Conclusions: The differences in OS observed in FIRE-3 are pronounced in time intervals between 24-30 months as well as 30-36 months after randomisation into the study. A small number of patients received rather short courses of anti-tumor therapy in these observation units. The significant difference in OS that manifests in time-frames between 24 and 30 months as well as between 30 and 36 months suggests that underlying effects on OS in FIRE-3 may include multiple factors and cannot be explained by the number of patients on active treatment alone. Clinical trial information: NCT00433927. [Table: see text]
The therapeutic effect of irreversible electroporation ablation in mouse model of gastrointestinal cancer.
Authors: Choi Hyuk Soon , Chun Hoon Jai , Yoo In Kyung , Lee Jae Min , Kim Seung Han , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Kim Chang Duck
Published: February 2017

62

Background: Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. IRE has an advantage over other ablation technique in its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, prostate, etc. and IRE is now accepted as a novel anti-cancer ablation modality. The aim of this study was to evaluate the therapeutic effect of IRE in mouse model of gastrointestinal cancer for the first time. Methods: The Caco2 cells (ATCC) were cultured in petri-dishes. Male nude mice (Immunodeficient (CAnN.Cg-Foxn1 nu/CrljBgi) 6 weeks old, Orient Inc., Korea) were introduced. Caco2 cells were each visually injected at 1.0 x 107cells/ml into both flakes (one for control, the other for IRE). We performed in vivo IRE procedures in the tumors of nude mouse model. Electrical pulses were applied to the tumor of nude mouse using a DC generator at 1~2kV/cm amplitude, 20~50 pulses, 100 µA length, with 1mm separation between two needle type electrodes. We analyzed the tissues with H&E staining and TUNEL assay immediately afterwards, and then 10 hours, 24 hours. Results: All mice were preserved during the experiment without significant complications. There was complete cell death within the IRE lesions without intervening live cells in 2KV after 24 hours. H& E statin and Tunnel stain at 10hr after 2KV IRE ablation revealed more severe apoptotic cell death comparing with control group. Apoptotic index peaks at 10 hours after IRE ablation, and decreases in 24hours. The framework of extracellular matrix and blood vessels were not affected by IRE. Conclusions: The present study demonstrated that IRE ablated colon cancer tissue very effectively through the induction of cellular apoptosis. This study suggests that IRE has the potentiality in treatment of gastrointestinal cancer patients.
Translational investigations of gastrointestinal malignancies using spheroid cultures.
Authors: Carchman Evie , Payne Susan , Pasch Cheri , Matkowskyj Kristina , Lubner Sam Joseph , Bassetti Michael F. , LoConte Noelle K. , Mulkerin Daniel , Deming Dustin A.
Published: February 2017

620

Background: Spheroid cultures are now being used to investigate the biology of multiple types of cancer. This technique allows for a cost-effective, efficient and reliable means to culture tissues of interest. Recent investigations have demonstrated that spheroids maintain high mutational concordance with the cancers they are derived. We sought to determine if spheroid techniques could be utilized to perform translational investigations into subtypes of gastrointestinal malignancies. Methods: Transgenic mice carrying conditional mutations in key genes known to have important roles in colorectal cancer (CRC) tumorigenesis and progression were treated with a Cre-expressing adenovirus to initiate tumorigenesis. The mutant genes of interest included Apc, Trp53, KRAS, Pik3ca, and/or BRAF. Biopsies of these cancers were obtained with the murine endoscope and the tissue processed for spheroid culture. In addition, transgenic E6 and E7 mice were treated with DMBA and the resulting anal squamous cell carcinomas were harvested for spheroid culture. Cultured spheroids were imaged to characterize growth rate and changes in architecture. In addition, studies assessing response to therapeutics were performed and correlated with in vivo response. Human operative specimens were also obtained for culturing. Results: Multiple lines of murine CRC spheroids were able to be generated with a greater than 90% efficiency rate. These cultures maintained phenotypic characteristics of the cancers from which they were derived. Bright field imaging pre- and post-treatment was able to be utilized for quantification of treatment response. The median relative change in spheroid diameter was compared across treatment groups and correlated with response in vivo. Heterogeneity in the response of individual spheroids to treatment strategies was detected with this method. Murine squamous cell anal carcinoma was spheroid lines were generated similarly. Human CRC and anal cancers were also generated with high efficiency. Conclusions: Spheroid cultures from CRC and anal cancers can be generated with high efficiency and hold great promise for furthering treatment options for patients with cancer.
Clinicopathological features of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in Japanese patients.
Authors: Kawazoe Akihito , Shitara Kohei , Noguchi Masaaki , Fukuoka Shota , Kuboki Yasutoshi , Bando Hideaki , Okamoto Wataru , Kojima Takashi , Doi Toshihiko , Ohtsu Atsushi , Yoshino Takayuki
Published: February 2017

629

Background: Recently, anti-programmed death 1 (PD-1) antibody has shown promising efficacy in a phase II trial for patients with microsatellite instability-high (MSI-H) tumors, especially in those with metastatic colorectal cancer (mCRC). Currently, several clinical trials of anti-PD-1 antibody for patients with MSI-H mCRC are ongoing. However, little is known about the frequencies and clinicopathological features of MSI-H mCRC in Japanese patients. Methods: Patients with histologically confirmed adenocarcinoma of mCRC were eligible for this observational study. MSI status was analyzed in tumors using the MSI Analysis System (Promega) composed of 5 mononucleotide markers. KRAS, NRAS, BRAF and PIK3CA mutations were also evaluated using the multiplex kit. Results: A total of 232 patients were enrolled until August 31, 2015, of which MSI-H was detected in 5 patients (2.1%). Among five patients with MSI-H mCRC, median age was 45 years (28-75), four had tumors on right-sided colon, five had moderately differentiated adenocarcinoma, one had poorly differentiated adenocarcinoma, and three had stage IV disease at presentation. Overall survival for patients with MSI-H mCRC from the start of first-line systemic chemotherapy ranged from 8.1 to 62.0 month. All five patients with MSI-H mCRC had RAS wild-type tumors and two had BRAF V600E mutation. One patient with MSI-H mCRC was enrolled in a phase II trial of anti-PD-1 antibody. Conclusions: MSI-H mCRC is rare in Japanese patients. A large scale nationwide cancer genome screening project together with MSI status is required to evaluate more detailed clinicopathological features and facilitate the enrollment of patients with MSI-H mCRC for clinical trials with anti-PD-1 antibody.
Prognostic impact of tumor-associated B-cells and plasma cells in esophageal and gastric adenocarcinoma.
Authors: Fristedt Richard , Hedner Charlotta , Borg David , Nodin Bjorn , Eberhard Jakob , Micke Patrick , Jirstrom Karin
Published: February 2017

63

Background: Tumor immune cell infiltration has been shown to influence the prognosis and treatment prediction in several types of cancer and the focus has largely been on the innate immune system as well as the cell-mediated immune response. There are, however, recent findings suggesting an important role for the humoral immune system in stemming cancer progression. The aim of this study was therefore to investigate the prognostic impact of B cell and plasma cell infiltration in esophageal and gastric cancer. Methods: Immunohistochemical expression of the pan B-cell marker CD20 and plasma cell markers CD138 and immunoglobulin kappa C (IGKC), were analyzed in tissue microarrays (TMA) from primary tumors in a cohort of 174 consecutive, surgically treated cases of gastro-esophageal adenocarcinoma. A multiplier of intensity and fraction was calculated, and the median value was used for prognostic cut-off. Kaplan-Meier analysis, univariable and multivariable Cox regression analysis, adjusted for age, TNM-stage, resection margins and adjuvant chemotherapy, were used to determine the impact of IGKC, CD20 and CD138 expression on overall survival (OS). Results: A high density of IGKC+ plasma cells was significantly associated with a prolonged survival in esophageal (HR 0.41, 95% CI 0.21-0.78) and gastric adenocarcinoma (HR 0.50, 95% CI 0.28-0.88). A high density of CD138+ plasma cells was also significantly associated with prolonged survival but only in gastric adenocarcinoma (univariable HR 0.48, 95% CI 0.27-0.86, multivariable HR 0.51; 95% CI 0.27-0.97)). IGKC+ plasma cell expression remained significant in multivariable analysis, for esophageal (HR 0.50, 95% CI 0.26-0.97) and gastric adenocarcinoma (HR 0.50, 95% CI 0.27-0.94). There was no significant association between the density of CD20+ cells and survival. Conclusions: Our findings show, for the first time, that a higher density of stromal plasma cells correlates with a prolonged survival in both esophageal and gastric adenocarcinoma. These are new and encouraging findings that warrant further evaluation in additional patient cohorts.
Effects of a structured exercise program on physical activity and health-related fitness in colon cancer survivors: One year feasibility results from the NCIC CTG CO.21 (CHALLENGE) trial.
Authors: O'Callaghan Christopher J. , Courneya Kerry S. , Vardy Janette L. , Friedenreich Christine , Campbell Kristin L. , Prapavessis Harry , Crawford Jennifer J , O'Brien Patti , Dhillon Haryana M. , Jonker Derek J. , Chua Neil Sun , Lupichuk Sasha M. , Sanatani Michael Susmoy , Gill Sharlene , Meyer Ralph M. , Begbie Stephen , Bonaventura Antonino , Burge Matthew E. , Tu Dongsheng , Booth Christopher M.
Published: February 2017

648

Background: There is strong interest in testing lifestyle interventions to improve cancer outcomes, however, the optimal methods for achieving behaviour change in large scale pragmatic trials are unknown. We report the 1 year feasibility results for behaviour change in NCIC CTG CO.21 Colon Health and Life-Long Exercise Change (CHALLENGE) Trial. Methods: Between 2009 and 2014, 273 high risk stage II and III colon cancer survivors who had recently completed chemotherapy at 50 centers in Canada and Australia were randomized to a structured exercise program (SEP n = 136) or health education materials (HEM n = 137). The primary feasibility outcome in an a priordefined interim analysis was a difference between groups of ≥ 5 metabolic equivalent task (MET) hours/week in self-reported physical activity (PA) after at least 250 participants had reached 1 year. Secondary feasibility outcomes included cardiorespiratory fitness, body weight and circumferences, and objective physical functioning. Results: The SEP group reported a mean increase from baseline to 1 year PA of 15.6 MET hours/week vs a mean increase of 5.1 in the HEM group (+10.5 hrs/wk [95% CI = +3.1 to +17.9]; p = 0.002). SEP also improved relative to HEM in mean differences for predicted VO2max (+2.2ml/kg/min; p = 0.068), 6 minute walk (+29m; p < 0.001), 30 second chair stand (+1.6reps; p < 0.001), 8 foot up and go (-0.4s; p = 0.004), and the sit and reach (+2.1cm; p = 0.08). Conclusions: The behaviour change intervention in the CO.21 Trial produced an increase in self-reported PA that exceeded the feasibility criterion for trial continuation, resulted in objective fitness improvements, and is consistent with the amount of PA associated with improved colorectal cancer outcomes in observational studies. Recruitment to CO.21 remains ongoing. Clinical trial information: NCT00819208.
Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin).
Authors: Kim Seung , Won Young-Woong , Kim Jung Hoon , Park Joon Ho
Published: February 2017

65

Background: The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin). Methods: We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8%). Results: Among 54 patients, the median age was 51.5 years (range, 23–72 years). Most patients were men (59.3%). Seven patients (13.5%) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among 7 patients with tumors with FGFR2 expression, 6 achieved partial response (PR) with a 85.7% response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5%). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, p = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS. Conclusions: FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx.
Impact of anti-VEGF therapy in metastatic colorectal cancer with an intact primary tumour.
Authors: Lee Belinda , Wong Hui-Li , Tie Jeanne , Wong Rachel , Lee Margaret , Nott Louise M. , Shapiro Jeremy David , Jennens Ross , Turner Natalie Heather , Tran Ben , Ananda Sumitra , Yip Desmond , Richardson Gary Edward , Parente Phillip , Lim Lionel , Stefanou Greg , Burge Matthew E. , Iddawela Mahesh Y. , Gibbs Peter
Published: February 2017

650

Background: The management of metastatic colorectal cancer (mCRC) with anti-VEGF therapy and a fluoropyrimidine-containing chemotherapy is well established in first and second line therapy. However the role, safety and benefits of anti-VEGF therapy (Bevacizumab) in specific subgroups including those with an intact primary tumour (IPT), are not well described. Methods: Consecutive mCRC pts enrolled from January 2009 were identified from a prospective multi-site Australian registry. Survival and key safety endpoints were explored for pts with an IPT versus pts with a resected primary (RPT). Differences in outcomes were compared using log-rank test and Kaplan-Meier curves. Results: Of 1,204 pts with mCRC, 826 (69%) eligible pts were identified. Anti-VEGF therapy use in the first-line setting was similar in pts with an IPT [200/313 (64%)] vs. a RPT [357/513 (70%)]. In both groups the addition of anti-VEGF therapy was associated with greater PFS; IPT 8.5 vs. 4.7 months (HR 0.73, p=0.017) and RPT 10.8 vs. 5.8 months (HR 0.67, p=0.0002). OS was longer in anti-VEGF treated pts; IPT 20 vs. 14.8 months (HR 0.66, p=0.0046) and RPT 24.4 vs. 17.3 months (HR 0.71, p=0.0039). A trend for more GI perforations with anti-VEGF therapy use was seen in pts with IPT (4.5% vs. 1.8%, p=0.33), but not RPT (1.7% vs. 1.9%). The rate of bleeding and thrombosis was lower in the IPT group treated with bev: 1.5% vs. 5.3%, p=0.05 and 1.5% vs. 2.7%, p=0.47 respectively. In comparison, RPT pts treated with and without anti-VEGF therapy had a bleeding rate of 3.4% vs. 0.6%, p=0.07, and a thrombosis rate of 5.9% vs. 0.6%, p=0.007. Conclusions: In routine clinical practice clinicians appear comfortable using anti-VEGF therapy in pts with an IPT. Superior PFS and OS outcomes were seen with addition of anti-VEGF therapy, with no evident impact of primary tumor status. There was a trend for a higher GI perforation rate in anti-VEGF treated IPT pts, but a lower rate of other adverse events. This may reflect clinicians avoiding anti-VEGF therapy in pts considered at increased risk of these complications. Further analysis is underway to explore this possibility.
Impact of comorbidities using Adult Comorbidity Evaluation-27 (ACE-27) score on survival in stage II colon cancer: Age, TNM staging, and pathological high risk-disease.
Authors: Amin Manik A. , Wang-Gillam Andrea , Tan Benjamin R. , Suresh Rama , Picus Joel , Singh Preet Paul , Lim Kian-Huat , Masood Ashiq , Lockhart Albert C.
Published: February 2017

659

Background: Impact of comorbidities is identified in stage III colon cancer patients (CCPs) receiving adjuvant chemotherapy (Wildes et al, PMID 21113435) but is not well defined in predicting overall survival (OS) in stage II CCPs undergoing either adjuvant treatment or observation depending upon high-risk disease. The goal of this study was to identify impact of comorbidities on OS in this potentially curable disease using ACE-27 score, which uses 27 different patient comorbid conditions has been developed and validated by Piccirrillo et al at Barnes Jewish Hospital (BJH) (PMID: 24933715). Methods: We identified stage II CCPs treated at BJH, Siteman cancer center from January 1, 1996 to October 31st, 2013 from BJH oncology data cancer registry. The primary outcome was OS, defined as the time from date of surgery to death from any cause, censored at the time of last follow-up. Patient comorbidities at diagnosis were recorded using ACE-27 score, assigning a comorbidity score of none, mild, moderate and severe to the patients. Survival analysis was done using Cox proportional hazard modelling using STATA/SE 11.2 software. Pathological high risk features such as T4 lesions, < 12 LN, perineural, lymphovascular invasion, positive margins & perforation/obstruction were identified. Results: Out of 579 stage II CCPs, 48% male and 51% were females. High risk features were identified in 45% of patients. ACE-27 comorbidity score of none (n = 146), mild (n = 229), moderate (n = 132) and severe (n = 72) was calculated. 497 patients had T3N0M0 and 82 had T4N0M0 staging. Cox regression hazard model using histological prognostic factors, age at surgery, sex, race, prior cancer history and TNM staging showed that ACE-27 score of moderate and severe were independent predictors of OS with a hazard ratio of 1.6 (95% CI 1.0-2.4), P = 0.036 and 2.5 (95% CI 1.5-4.0), P = 0.00 respectively. Conclusions: Highest commodity burden using ACE-27 comorbidity score was associated with poor OS in stage II CCPs and was independent of other prognostic risk factors including high-risk features. Treatment related mortality will be calculated in patients with high risk disease.
Chemotherapy (Ctx) use and adoption of new agents in older versus younger patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Vijayvergia Namrata , Li Tianyu , Wong Yu-Ning , Hall Michael J. , Cohen Steven J. , Dotan Efrat
Published: February 2017

674

Background: The treatment of mCRC has changed substantially in the last 2 decades but adoption of new drugs has not been well studied in older pts. We explored the effect of age and comorbidities on the adoption of irinotecan (Iri) and oxaliplatin (Ox) in mCRC pts over a 15 year timespan. Methods: mCRC pts receiving 5-Fluorouracil (5FU) based Ctx between 1995-2009 were studied using the LifeLink Health Plan Claims Database, and evaluated based on age (>70 vs ≤70y). Pts were identified by ICD-9 / HCPCS (J) codes. The fraction of pts receiving Ctx was calculated at yearly intervals and any other agent received with 5FU defined combination Ctx. Charlson Comorbidity Index (CCI) was used to assess comorbidity burden. Wilcoxon's and χ2test were used in univariate and logistic regression in multivariate analyses (MVA). Results: 16087 pts were identified with a median age of 61y and 55% males. The difference in proportions of older vs younger pts receiving Ctx for mCRC remained stable over the 15 year period. There was an increase in the fraction of pts with CCI>1 over time (14% in 1996; 40% after 2004 (p<0.05). Older pts had higher rate of CCI>1 (Table). Use of single agent 5FU declined in both groups over time. After FDA approval, use of Iri was lower in older pts (15 vs 38% in 1998, p<0.05), but this difference resolved by 2002 (62% both groups, p=0.9). Similarly, Ox was used more frequently in younger pts after initial approval (15% vs 22% in 2003), with decrease in this difference by 2009 (60% vs 64%,p=0.9). Older pts were less likely to get >2 agents when compared to younger (15 vs 22%, 29 vs 39% and 11 vs 16% in 2003, 2006 & 2009 respectively, p<0.001). On MVA, likelihood of receiving combination Ctx increased over time [OR 1.2; 1.18-1.26; p<0.01], but was lower in older pts [OR 0.65;0.59-0.71, p<0.001] and pts with CCI>1 [OR 0.84;0.77-0.91; p<0.001]. Conclusions: In a group of commercially insured pts, a lower fraction of older pts are treated for mCRC and adoption of new agents into the treatment of older pts appears to lag behind that of younger pts. However, oncologists have become more comfortable treating older pts with comorbidities over time. [Table: see text]
Impact of prophylactic treatments of cetuximab-based skin reactions in patients with metastatic colorectal carcinoma (mCRC): Interim analysis of the German noninterventional study ERBITAG.
Authors: Sahm Stephan , Goehler Thomas , Hering-Schubert Christiane , Janssen Jan , Schwittay Michael , Zahn Mark-Oliver , Stenzel Karsten Guenter , Steinbach-Buechert Alma Katharina , Overkamp Friedrich
Published: February 2017

675

Background: Prophylactic treatments are widely used to ameliorate skin reactions induced by EGFR inhibition. Randomised studies have shown a positive impact of prophylactic antibiotics. Methods: Patients (Pts) with KRAS-wt and later RAS-wt mCRC treated with a first-line chemotherapy regimen plus cetuximab with written informed consent were eligible for this prospective, non-interventional study. Physicians were requested to complete a questionnaire and document any applied prophylactic and reactive skin toxicity treatment for every pt. Different prophylactic treatment regimens were categorized in 5 groups: systemic antibiotics (SA), skin care without antibiotics or corticosteroids (SC), other topical treatments (OT) (e.g. antibiotics or corticosteroids), any prophylaxis (P), and no prophylaxis (NP). Results: Data from 497 pts at 178 centers were finally collected and evaluable at data cut off. For all reported skin reactions the maximum NCI-CTCAE grade per patient and prophylactic treatment group was evaluated (table). Although none of the prophylactic regimens were significant different from NP, SA showed a numerically lower rate of all skin reactions by 8.1% (p=0.06) and of rash acneiforme by 5.3% (p=0.134) versus NP. 96.2% of reactive treatments of skin toxicities were done without consultation of a dermatologist and the medication was topical or systemic in 60.9% and 32.3%, respectively. Response to reactive treatment was complete remission or significant improvement of the skin reactions in 68.6% (topical) and 66.0% (systemic). Conclusions: Pts given prophylactic SA showed numerically fewer grade 3-4 skin reactions in comparison to NP (7.6% vs. 15.7%), but without significance. An important reason for failing significance may be the low number of pts receiving prophylactic SA (only in 18.5% of pts). Reactive treatment (systemic or topical) of skin toxicities led to an improvement in the majority of pts. Clinical trial information: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_455. [Table: see text]
Clinicopathologic characteristics that affect the treatment and recurrence of rectal carcinoid tumor in Korea.
Authors: Lee Dong Ho , Park Young Soo , Hwang Jae Jin , Jung Hyun chae
Published: February 2017

684

Background: The increase of colonoscopy procedures has led to an increase in the diagnosis of rectal carcinoid tumors. The aim of this study was to evaluate the clinical and pathological characteristics that affect the treatment and recurrence of rectal carcinoid tumors. Methods: Between 2003 and 2014, the medical records of patients with rectal carcinoid tumors were retrospectively reviewed. Patient and tumor characteristics, treatment and recurrence were analyzed. Results: The mean age was 51.7 ± 11.7 (range, 22-80 years) and the male to female ratio was 1:0.58. The mean tumor size was 8.7 ± 4.9 (3-27) mm. Four hundred-seven out of 424 patients were treated by endoscopy (mean size of tumor: 8.6 ± 3.6 mm) and 17 were treated by surgery (mean size of tumor: 12.5 ± 5.7 mm, p = 0.023). However, the histology showed that 87 patients treated by endoscopy had positive resection margins; 68 cases (16.0%) had a polypectomy and 19 cases (4.4%) had a endoscopic mucosal resection (p = 0.033). The mean follow-up duration was 29.1 ± 31.3 months, and there were five recurrences of rectal carcinoid tumors.All cases of recurrence of rectal carcinoid tumor were successfully re-treated by additional endoscopic resection. Conclusions: Endoscopic resection was an effective method for the treatment of rectal carcinoid tumors. Moreover, even for small rectal carcinoid tumors, follow-up examination should be performed to evaluate for tumor recurrence.The recurrence of rectal carcinoid tumor should be successfully controlled by additional endoscopic resection.
Innovation or disparity? National trends in nonoperative management of rectal adenocarcinoma.
Authors: Ellis Clayton Tyler , Samuel Cleo A. , Stitzenberg Karyn B.
Published: February 2017

688

Background: While surgical resection has always been the cornerstone of curative treatment for rectal cancer, preoperative chemoradiation for stage II/III rectal cancer results in up to 49% of patients with a clinical complete response. As a result, many have questioned whether surgery can be omitted for this group of patients. Currently, there is insufficient evidence on the safety and efficacy of chemoradiation-only, or non-operative management (NOM), to support the wholesale adoption of this treatment paradigm. Despite this, anecdotal evidence suggests there is a trend for increased use of NOM. Our objective was to examine trends in the use of NOM for rectal cancer over time as well as patient- and facility-level factors associated with its use. Methods: We included all incident cases of invasive, non-metastatic, rectal adenocarcinoma reported to the National Cancer Data Base (NCDB) from 1998–2010. We performed univariate and multivariate analyses to assess NOM use over time as well as patient- and facility-level predictors of NOM. Results: 146,135 patients met inclusion criteria: 5,741 had NOM and 140,394 had surgery +/- additional therapy. From 1998-2010, the use of NOM doubled from 2.4% to 5% of all cases annually. Patients who were Black (AOR=1.71, 95%CI=1.57-1.86), uninsured (AOR=2.35, 95%CI=2.08-2.65), Medicaid-enrolled (AOR=2.10, 95%CI=1.90-2.33), and those treated at low-volume facilities (AOR=1.53, 95%CI=1.42-1.64) were more likely to receive NOM than White, privately insured, and high-volume facility patients, respectively. Additionally, NOM was more common in the South (AOR=1.53, 95%CI=1.32-1.76) and Pacific (AOR=1.82, 95%CI=1.57-2.12) as compared with the Northeast. Conclusions: NOM is an innovative approach that demonstrate promise in the treatment of rectal cancer. Pursing this approach in the context of a clinical trial and with well-informed patients would be appropriate. We observed evidence of increasing NOM utilization; however, this increase is occurring more frequently in Black and uninsured/Medicaid patients, raising concern that increased NOM use may actually represent increasing disparities in rectal cancer care rather than innovation.
Changes in treatment patterns for patients with locally advanced rectal cancer in the United States over the past decade: An analysis from the National Cancer Data Base (NCDB).
Authors: Sineshaw Helmneh M. , Jemal Ahmedin , Mitin Timur
Published: February 2017

691

Background: Neoadjuvant chemoradiation therapy (NACRT) is widely accepted as the standard of care for treatment of locally advanced rectal cancer in the United States. We sought to examine patterns of treatment for locally advanced rectal cancer in US over the past decade. Methods: Using the National Cancer Data Base (NCDB), we identified 66,197 patients diagnosed with stage II-III rectal adenocarcinoma and treated between 2004 and 2012. We described trends in receipt of treatment based on aggregated data for three time periods (2004-2006, 2007-2009, 2010-2012), using trend test. We analyzed 5-yr overall survival (OS) probabilities for 28,550 patients treated between 2004 and 2007. Results: Receipt of NACRT increased significantly over the past decade from 42.9% in 2004-2006 to 50.0% in 2007-2009, and then to 55.0% in 2010-2012 (p < 0.0001). In contrast, use of adjuvant chemoradiation (CRT) decreased steadily from 16.7% in 2004-2006 to 10.5% in 2007-2009, and then to 6.7% in 2010-2012 (p < 0.0001). Similarly, treatment with surgery alone decreased from 13.1% in 2004-2006 to 8.7% in 2010-2012 (p < 0.0001). Older age, presence of comorbidities, larger primary tumor size, lymph node involvement, non-Hispanic white ethnicity, lack of private insurance, and being treated at a non-high case volume facility were associated with a significantly lower chance of receiving NACRT in multivariable logistic regression analysis. 5-yr OS probabilities for patients treated with NACRT, surgery and adjuvant CRT, surgery alone, and definitive CRT were 72.4%, 70.9%, 44.9% and 48.8%, respectively. Conclusions: Utilization of NACRT prior to surgery in US patients diagnosed with locally advanced rectal cancer has substantially increased over the past decade. However, only about half of these patients currently receive the standard therapy as recommended by national guidelines, and there may be social and economic barriers to receiving the standard of care. Tri-modality therapy is associated with the best outcomes for these patients, and surgery alone or definitive chemo-radiation should only be reserved for patients unable to tolerate tri-modality therapy.
Which is the better prognostic factor in rectal cancer patients who received neoadjuvant chemoradiotherapy: cTNM stage vs. ypTNM stage?
Authors: Kim HyungJin , Kim Gun , Yoo Ri Na , Kye Bong-Hyeon , Cho Hyeon-Min
Published: February 2017

693

Background: Neoadjuvant chemoradiotherapy (nCRT) in rectal cancer is widely applied in patients with cTNM II and III stage. However, it is still obscure which staging system, either clinical (c) or pathologic (yp), influences in prognosis. This study aims to evaluate the current staging system predicting prognosis in the locally advanced rectal cancer patients. Methods: Among 221 patients who were diagnosed with rectal cancer and underwent curative resection from January 2009 to February 2013, 141 patients who received nCRT were included. The ypTNM stage was categorized: complete remission and stage I to ypI. Results: Mean follow-up period was 36.3 ± 15.1 months. Disease-free survival (DFS) was not associated with age, sex, Anesthesiologists classification, types of operative procedure, tumor cell differentiation, tumor location, tumor infiltration, preoperative CEA level, adjuvant chemotherapy. cTNM stage did not demonstrate any correlation with DFS (cII % vs cIII %, P = 0.266). However, DFS did exhibit statistically significant association with postoperative CEA level (P < 0.001) and ypTNM stage. 3-year DFS rate for each categorized stage is as followed – ypI, 87.9%; ypII, 67.8%; ypIII, 53.3% (ypI vs. ypII P = 0.009, ypI vs. ypIII P < 0.001, ypII vs. ypIII P= 0.185). Conclusions: Oncologic outcome of the patients with locally advanced rectal cancer is associated with pathologic TNM stage. Based on our results, we think that adjuvant chemotherapy given to patients with complete remission or pathologic stage I may be reconsidered.
Fiducial markers vs. PET/CT for esophageal cancer GTV delineation for radiotherapy treatment planning using a standard SUV threshold and background uptake method.
Authors: Oliver Jasmine A , Venkat Puja , Montilla-Soler Jaime , Klapman Jason , Dhadham Gautumy Chikiti , Harris Cynthia L. , Emanuel Karen , Werner Joan , Jin Will , Frakes Jessica M. , Dilling Thomas J. , Zhang Geoffrey , Moros Eduardo G , Hoffe Sarah E. , Latifi Kujtim
Published: February 2017

70

Background: Often in esophageal targets that move with respiration, endoscopically implanted fiducial markers are placed under ultrasound guidance within 1 cm from the superior and inferior tumor border. Our group has previously reported the stability of this method. 3D 18F-FDG PET/CT is obtained for initial staging of esophageal cancer and has altered the tumor volume in many sites. The correlation of these two methods for GTV delineation is currently undefined. Methods: Twenty-one patients with esophageal cancer were selected for this retrospective, IRB-approved analysis. Each patient underwent fiducial placement (by one of six endoscopists) at the inferior and superior borders of the tumor and received PET/CT prior to Radiotherapy (RTx). PET/CT images were imported into an image analysis software system for measurements. The distance between fiducial markers and MTV defined by 2.5 SUV contour (method 1) and MTV using a threshold above mean liver uptake (method 2) was calculated. The fiducials were located on CT. The distance between the centroid and MTV border was measured. The Concordance Correlation Coefficient (CCC) was calculated to determine the correlation between results from the two methods. Results: In method 1 the median distance between MTV (2.5 SUV) and fiducials was 1.0 cm (0.0 cm - 2.8 cm) and 1.0 cm (0.0 cm - 6.9 cm) for inferior and superior borders, respectively. In method 2 median distance between MTV and fiducials was 1.14 cm (0.0 cm - 2.62 cm) and 1.64 cm (0.33 cm – 6.84 cm) for inferior and superior borders, respectively. The CCC indicated poor agreement between methods for both distances (0.57 and 0.87 for inferior fiducial distance and superior fiducial distance, respectively). There was no correlation between MTV-to-fiducial distances greater than 2 cm and the endoscopist that performed the fiducial implantation. Conclusions: Although the methods of defining the MTV had poor strength of agreement, both methods demonstrated a robust correlation between inferior fiducial marker placement and inferior PET/CT uptake. The superior fiducial marker and MTV border illustrated discordance – unrelated to the endoscopist.
The clinical trial for photodynamic diagnosis mediated 5-ALA for peritoneal metastasis due to advanced gastric cancer.
Authors: Takahashi Tsuyoshi , Miyazaki Yasuhiro , Makino Tomoki , Kurokawa Yukinori , Yamasaki Makoto , Takiguchi Shuji , Nakajima Kiyokazu , Mori Masaki , Doki Yuichiro
Published: February 2017

71

Background: In advanced gastric cancer, the diagnosis of peritoneal metastasis is mandatory prior to the decision of therapy, therefore staging laparoscopy (SL) has gained wider clinical acceptance. However, a false-negative rate of 10% using SL has also been reported, which demonstrates the limitation of optical observation for the dissemination of the cancer nest. Photodynamic diagnosis (PDD) by 5-aminolevulinic acid (ALA) has been proposed for peritoneal metastasis in SL and showed higher sensitivity than that of conventional examination. To evaluate effectiveness and safety of ALA-PDD for the diagnosis of the peritoneal disseminations. Methods: Thirteen advanced gastric cancer that had the signs of peritoneal metastasis pointed out by CT scan prior to the treatment were included. Patients were administered 5-ALA (1g/body) orally 4hours prior to the SL. Several lesions regulated to observe bilateral sub- phrenic peritoneum, bilateral flanks and Douglas’s pouch (conventional examination, PDD each). If the nodules suspected for the metastatic lesion were found, they were diagnosed by laparoscopic biopsy. We evaluate the potential of additional detection rate compared to the conventional examination and safety. Results: The patients characters were as below, gender (male: female) = 8:5, Age (median; range) = 69 years old (39-76). The TNM factor were that cT3:4a = 2:11, cN0:1:2:3 = 2:0:7:4, cM0:1 = 10:3(Japanese classification of gastric carcinoma: 3rd English edition).The additional detection rate was 8.3 %( 1/13) and the incidence of adverse effect was 8.3 %( nausea, Grade 1). Conclusions: The ALA-PDD was effective and safe examination for the peritoneal metastasis of gastric cancer. And furthermore, we are now going to conduct the new investigator initiated trial.
Weekly bolus 5-fluorouracil and bevacizumab in the palliative treatment of metastatic colorectal cancer.
Authors: Cook Michelle Jane , Connor Carole , Khan Mohammed Mojid , Correa Peter Denzil
Published: February 2017

736

Background: Patients with metastatic colorectal cancer (mCRC) are often elderly with multiple co-morbidities making them poor candidates for combination chemotherapy. Evidence suggests significant benefit from the addition of Bevacizumab (Bev) to single agent fluoropyrimidine chemotherapy in the palliative treatment of mCRC. There is no current trial data to support use of weekly bolus 5-fluorouracil (5-FU) chemotherapy combined with Bev. We present details of our experience with this treatment regimen. Methods: Patients with mCRC treated with weekly bolus 5-FU 370 mg/m2and Bev 5mg/kg every 2 weeks (Weekly-5FU-Bev) as a new line of palliative treatment were reviewed. All were deemed unsuitable for Capecitabine. Data were collected retrospectively from patient records. Survival statistics were calculated from date of treatment initiation using Kaplan-Meier methods. Results: From 2012-2015, 21 patients were treated with Weekly-5FU-Bev. Median age was 80 years (range 56-90 years), 57.1% were performance status (PS) 0, 19% PS 1 and 23.8% PS 2. 61.9% patients were Ras wild-type. Median treatment duration to date is 20 weeks (range 4-117 weeks). Treatment was stopped in 8 due to progressive disease, 1 due to toxicity and 4 for other reasons. Treatment was generally well tolerated with significant fatigue the most commonly reported side effect in 24%. 3 patients experienced venous thrombo-embolic events, 1 developed uncontrolled hypertension and 1 suffered a non-fatal tumour perforation. There were no treatment related deaths. Clinical benefit rate determined by best response to treatment was impressive at 66.7% with 1 complete response, 1 partial response, 1 biochemical response (non-measurable disease) and 12 patients with stable disease. Median progression free survival was 9.3 months (95% CI 2.8-15.8 months). Median overall survival has not been reached with 15 patients still alive. Conclusions: Acknowledging the limitations of this retrospective analysis of a carefully selected patient group, Weekly-5FU-Bev appears to be well tolerated and efficacious in the treatment of elderly patients with mCRC and can be considered an option in patients unsuitable for or intolerant of Capecitabine.
Metastatic lymph node ratio as an independent prognostic factor in stage III gastric cancer after D2 nodal dissection.
Authors: Ying Jieer , Li Cong , Zhang Yigong , Xu Qi
Published: February 2017

738

Background: The aim of this study was to evaluate the prognostic impact of metastatic lymph node ratio (MLR) in stage III gastric cancer after D2 dissection, and to assess the value of MLR for adjuvant chemotherapy. Methods: A total of 87 patients who underwent radical resection with D2 lymphadenectomy between December 2007 and March 2014 was enrolled in this study. Survival was determined by Kaplan-Meier method and survival curves were assessed by log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. Results: The median age of patients was 60 (range:21 to 83) with a male to female ratio of 2. 83 patients have undergone total gastrectomy (95.4%) and 4 subtotal gastrectomy (4.6%). 57 patients received chemotherapy, including 24 neoadjuvant chemotherapy and 33 adjuvant chemotherapy. All chemotherapy regimens have contained Flouropyrimidines (5-FU or capecitabine). There were only 5 patients received single-agent 5-FU or capecitabine as chemotherapy regimen, while 52 patients received combined-chemotherapy. The median total retrieved lymph node was 35 (range:10 to 104) and the median metastatic lymph nodes was 8 (range: 0 to 71). MLR was classified into 4 groups as follows: Group 1(MLR = 0), Group 2(MLR < 0.1), Group 3(MLR = 0.1-0.25), Group 4(MLR > 0.25). After a median follow-up of 28 months, the median PFS of group 1-4 was 37.1m, 35.9m, 31.5m and 16.9m, respectively (p = 0.025). The median PFS was significantly different in subgroups: 39.2m in low group (MLR < 0.25) with adjuvant chemotherapy, 36.4m in low group without chemotherapy, 17.2m in high group (MLR > 0.25) with chemotherapy and 11.5m in high group without chemotherapy (p = 0.012). The MLR was retained as an independent prognostic factor in multivariable analysis. Conclusions: After R0 resection with D2 lymphadenectomy for stage III gastric cancer, MLR can be a more effective and prognostic indicator. Patients with high MLR may most benefit from adjuvant treatments.
KRAS gene amplification to define a distinct molecular subgroup of gastroesophageal adenocarcinoma.
Authors: Henderson Les , Xu Peng , O'Day Emily , Cecchi Fabiola , Blackler Adele , Liao Wei-Li , Hembrough Todd A. , Catenacci Daniel V.T.
Published: February 2017

74

Background: KRAS mutation is rare ( < 5%) in gastroesophageal cancer (GEC). However, the incidence of KRAS gene amplification (amp+), consequent protein levels, and prognostic and/or therapeutic implications are unknown. Methods: 410 GEC samples and 30 cell lines were assessed for KRAS gene copy number (GCN) by fluorescence in situ hybridization (FISH) (n = 90), Kras expression by selected reaction monitoring mass spectrometry (Kras-SRM-MS) (n = 393), and Kras-SRM level evaluated for correlation with KRAS amp+ status (n = 73). Survival analysis was performed comparing KRAS amp+ versus non-amp+ patients. When possible, concurrent 315 gene next-generation sequencing was also performed. Four KRAS-amplified xenograft lines (CAT-2,12,14,15) were established from malignant effusions. Tumorigenic activity of KRAS amp+ lines (CAT lines, MKN-1) were assessed using MTT and soft agar assays in vitro and subcutaneous xenograft models, compared to non-amp+ lines. Inhibitory assays were performed using KRAS siRNA and CRIPSR, and commercial inhibitors targeting downstream effectors MEK and/or PIK3CA. Results: KRAS FISH revealed clustered gene amp+ in 28.9% (26/90); these patients had worse prognosis than non-amp+ patients. GCN significantly correlated with Kras expression. All KRAS amp+ cell lines significantly overexpressed Kras protein and were tumorigenic in xenograft subcutaneous models. KRAS siRNA and KRAS CRISPR of KRAS amp+ cell lines demonstrated inhibition in MTT viability and soft agar assays, compared to appropriate controls, and demonstrated significant and durable xenograft growth reduction. Conversely, inhibition using MEK and/or PI3K inhibitors demonstrated only transient growth reduction in vivo. Conclusions: KRAS gene amp+ was observed in a large subset (26%) of GEC patients, which correlated with extreme expression by mass spectrometry. Established xenograft lines serve as models to investigate therapeutic strategies for KRAS amp+ patients. Inhibition using MEK/PIK3CA inhibitors provided transient benefit for KRAS amp+ tumors while durable inhibition was observed with Kras protein knockdown, suggesting potential benefit from novel siRNA therapeutics currently in development.
Observational cohort study of 1st line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by the GERCOR index.
Authors: Muto Osamu , Yuki Satoshi , Muranaka Tetsuhito , Kato Takashi , Meguro Takashi , Nakamura Michio , Sato Atsushi , Iwanaga Ichiro , Uebayashi Minoru , Tateyama Miki , Hatanaka Kazuteru , Eto Kazunori , Okuda Hiroyuki , Sogabe Susumu , Abe Masakazu , Kato Kanji , Kato Sosuke , Miyashita Kencho , Sakata Yuh , Komatsu Yoshito
Published: February 2017

743

Background: The GERCOR index based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, the validity of the GERCOR index has not been reported in patients treated with bevacizumab (Bev)-based first line chemotherapy. Methods: 115 patients with mCRC treated with Bev contained first line chemotherapy were registered from 15 centers in Japan. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 108 patients. Patients with the GERCOR index of low, intermediate and high risk were 45, 57, and 6, respectively. The pts characteristics between low risk (L) and intermediate/high risk (I/H) were generally balanced except for prior colorectomy (75.6% in L, 54.0% in I/H; p = 0.027), based cytotoxic agent (oxaliplatin) (80.0% in L, 93.7% in I/H; p = 0.039), liver metastasis (53.3% in L, 79.4% in I/H; p = 0.006) and median number of metastatic organ (1 in L, 2 in I/H; p = 0.024). The distribution and median OS / PFS for the GERCOR index were as follows: L (n = 45; 29.9/10.0 months), I/H (n = 63; 17.0/8.5 months). For OS, there was significant difference between L and I/H (p = 0.003). For PFS, there was not significant difference between L and I/H (p = 0.522). In the Cox multivariate analysis, GI did not show an independent prognostic impact (L vs I/H ; HR 1.499, p = 0.120) and predictive impact (L vs I/H ; HR 0.922, p = 0.733). Conclusions: In this analysis, the GERCOR index might be neither the predictive nor prognostic factor in the bevacizumab combined first line chemotherapy for patients with mCRC.