bluuebunny/crossref_metadata_2025 huggingface dataset:
A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab (bev) as a first-line therapy for patients with metastatic colorectal cancer.
Authors: Sato Yasushi , Ohnuma Hiroyuki , Hirakawa Masahiro , Takahashi Minoru , Osuga Takahiro , Takada Kohichi , Hayashi Tsuyoshi , Sato Tsutomu , Miyanishi Koji , Takimoto Rishu , Kobune Masayoshi , Okita Kenji , Furuhata Tomohisa , Hirata Koichi , Kato Junji
Published: February 2017

612

Background: In a recent study by Loupakis, F. et al. (ASCO-GI 2013), a FOLFOXIRI and bevacizumab regimen showed promising activity and conversion rate in patients (pts) with metastatic colorectal cancer (mCRC). In order to evaluate a treatment regimen that was easier to administer, we conducted a dose-escalation study to determine the recommended dose (RD) of irinotecan (IRI) in combination with oxaliplatin and capecitabine and bevacizumab (XELOXIRI/bev) in pts with mCRC. Methods: Pts were eligible if they had mCRC (liver and/or other metastases), ECOG PS 0-1, were either negative or heterozygous for UGT1A1*6 or UGT1A1*28 and were not pretreated for metastatic disease. Treatment consisted of oxaliplatin (100 mg/m2 day 1), capecitabine (1700 mg/m2/day from day 2 to 15), IRI (100,120,150 mg/m2 for dose levels 1, 2, or 3, day 1) and bev (7.5 mg/kg, day 1), repeated every 3 weeks. The dose of IRI was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs were observed in six pts. If the MTD was not reached at the planned dose levels, the RD of IRI was defined as 150mg/m2, which is the maximum dosage approved for use in Japan. Results: 12 pts (F/M: 4/8, median age: 58 years, PS 0/1: 11/1) received a median of 6 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, which was observed in 1 of 6 pts at dose level 2. MTD was not reached at dose level 3. Therefore, the RD of IRI was defined as 150 mg/m2. Most common grade ≥ 3 toxicities were neutropenia (58.3%), anemia (16.6 %), diarrhea (8.3%), and febrile neutropenia (8.3 %). The response rate was 83.3%(95% CI 60-89), including 1 CR, 9 PRs. The disease control rate was 100%(95% CI 80-100). At a median follow-up of 8 months, median PFS was 15 months and median OS was not yet reached. Conclusions: XELOXIRI/bev is a feasible regimen; neutropenia was the DLT; recommended dose of IRI is 150 mg/m². The observed response rate of 83.3% is very promising and warrants further investigation. Clinical trial information: UMIN000005440.
Does interval from histologic diagnosis (Dx) to start of chemotherapy (Ctx) impact survival in metastatic colorectal cancer (MCRC)?
Authors: Jayaram Anuradha , Teo MinYuen , Keegan Niamh , Harrold Emily , Coleman Niamh , Kennedy M. John
Published: February 2017

615

Background: Optimal timing from colorectal surgery to initiation of adjuvant chemotherapy is between 4 to 6 weeks based on recent data. In MCRC, therapeutic benefits of ctx are frequently calculated from start of treatment. We investigated whether the interval between dx and commencement of ctx influences overall survival (OS) in patients (pts) with MCRC. Methods: Pts with CRC were identified from the institutional database. Inclusion criteria were MCRC and receipt of ctx. Clinicopathologic details were collected. Intervals from histologic dx to ctx were calculated. Analyses were based on receipt of ctx within 4 weeks (w), 5-8w and > 8w of dx. Survival was compared between groups. OS was presented as hazard ratio (HR) with associated p value. Results: Between 2003 and 2013, 123 pts were identified, where 58 pts receive ctx within 4w, 38 within 5-8w and 27 > 8w. Median OS (mOS) was 8.7, 15.7 and 13.7 months (mths) respectively. Improvement in OS was noted in pts treated 5-8w and >8w compared to within 4w (HR 0.53, 0.45; p=<0.01, <0.01). Surgical resection of the primary was noted in 14% of pts receiving ctx in 4w, 45% between 5-8w and 70% > 8w and mOS amongst these groups were 19.5, 16.3, and 22.1 mths respectively versus 6.5, 10.5 and 8.9 mths in similar groups without surgery. Improved OS in resected pts is noted in when treated 5-8w and > 8w compared to 4w (HR 0.76, 0.72 p= 0.55, 0.46) with no difference in OS between groups treated at 5-8w and > 8 w (HR 1.06, p= 0.85). Univariate and multivariate analyses for 5 variables are described in the Table, two of which are statistically significant on multivariate analyses. Conclusions: Our data did not suggest a detrimental effect on OS from ctx delay and the lack of survival benefit from early ctx might be due to a number of confounding variables as described above. [Table: see text]
Neoadjuvant chemoradiotherapy for locally advanced rectal cancer: Predicting long-term outcomes based on response to treatment.
Authors: Laws Kirsten Elizabeth Jean , Wilson Christina , McIntosh David , Harrow Stephen
Published: February 2017

621

Background: Neoadjuvant long course chemoradiotherapy is well recognised as a standard treatment in locally advanced, margin threatening rectal cancer, in order to downstage and reduce local recurrence. We investigated retrospectively whether long term outcomes could be predicted by response to neoadjuvant treatment, and which factors specifically seemed to predict a risk of poorer outcome. Methods: All patients treated with long course chemoradiotherapy between January 2008 and December 2009 were identified retrospectively. Patients were excluded if the treatment indication was for inoperable disease, postoperative, recurrence, or palliative intent. A total of 231 patients were analysed with retrospective analysis of all electronic records and case notes. The following information was collated: preoperative staging, chemoradiotherapy treatment planned and received, operation performed, postoperative pathology (including nodal status, margins, presence of LVSI, and evidence of response to neoadjuvant treatment), disease free survival, and overall survival. Results: Kaplan Meier curves are presented showing patients with either a complete or partial response to neoadjuvant treatment appear to have a statistically significant improvement in long term outcomes, compared to those with no response (Mean survival 55 months, 56 months and 43months respectively, p<0.01). Furthermore, those who remain node positive or have evidence of LVSI following neoadjuvant treatment appear to have a statistically significant poorer outcome. Conclusions: Our study further develops on previous work looking at the prediction of outcomes following response to neoadjuvant treatment in rectal cancer. It appears that those who respond to initial treatment will have a better outcome than those who do not, including those who remain node positive or with LVSI following treatment. This study is limited because it is retrospective. Randomised controlled trial data is required to enable identification of poor risk imaging and pathology features that might suggest the need for adjuvant therapy following combined modality treatment with neoadjuvant chemoradiotherapy and surgery.
The safety of chemotherapy for colorectal cancer patients with hepatitis C virus infection.
Authors: Tomizawa Kenji , Suyama Koichi , Miura Yuji , Shimomura Akihiko , Hanaoka Yutaka , Toda Shigeo , Moriyama Jin , Matoba Shuichiro , Takano Toshimi , Kuroyanagi Hiroya
Published: February 2017

629

Background: Hepatitis C virus (HCV) infection is one of the most common blood-borne infection in the world, and with an estimated to be infected more than 880,000 people in Japan. Little is known about the changes of HCV status during chemotherapy and the influence of HCV infection on toxicity of chemotherapy. Methods: We reviewed all patients diagnosed with colorectal cancer in our institution between 2001 and 2012 who had been screened for HCV infection by testing for anti-HCV antibody and identified 77 HCV-infected patients. We retrospectively analyzed the change in HCV load and the toxicities of chemotherapy in these patients. Results: Twenty-four of the 77 HCV-infected patients with colorectal cancer had received chemotherapy.The median age was 66 years (range: 42-80 years). Four patients had liver cirrhosis at the initiation of chemotherapy. The remaining 20 patients were diagnosed with chronic hepatitis, and their liver function tests and complete blood cell counts at baseline were normal. First-line chemotherapy included 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (n = 6), S-1 and irinotecan (IRIS) (n = 1), tegafur-uracil (n = 14), capecitabine (n = 1), capecitabine and oxaliplatin (XELOX) (n = 2).Serum HCV-RNA levels both before and after chemotherapy were evaluated in 10 patients, and the median serum HCV-RNA level before and after chemotherapy was 4.0 and 3.05 logIU/ml, respectively. Transaminase levels were elevated during chemotherapy in 2 patients. There were no patients suffered from grade 3-4 neutropenia or febrile neutropenia. Conclusions: This study indicates that chemotherapy can be safely performed in HCV-infected patients with colorectal cancer without change in HCV load.
Reintroduction of oxaliplatin for patients with metastatic colorectal cancer refractory to standard chemotherapy regimens.
Authors: Sasaki Tohru , Azuma Mizutomo , Koizumi Wasaburo , Egawa Tomohisa , Nagashima Atsushi , Kenmochi Takeshi , Shimada Ken , Takinishi Yasutaka , Kobayashi Kouji , Saito Yusuke , Akatsuka Sotaro , Arioka Hitoshi , Nakayama Norisuke , Nishimura Ken , Takagi Seiichi , Shirahata Atsushi , Soda Hitoshi
Published: February 2017

630

Background: Reintroduction of oxaliplatin seems to have clinical benefits for patients with metastatic colorectal cancer refractory to standard chemotherapy regimens. A interim analysis of RE-OPEN study reported 38.9% of disease control rate (DCR) in ASCO GI 2013, but it is still unknown who will receive benefits from reintroduction of oxaliplatin. Methods: Among patients in whom oxaliplatin was reintroduced in the 7 participating hospitals, we retrospectively studied patients who had previously received oxaliplatin and irinotecan and patients who had a response of stable disease or better during initial treatment with oxaliplatin. Results: From June 2009 through January 2013, oxaliplatin was reintroduced in 53 patients (31 men and 22 women). The median age was 64 years, and the performance status was 0 in 24 patients and 1 in 29. The reasons for discontinuing initial treatment with oxaliplatin were progressive disease in 36 patients, adverse events in 14 and others in 3. The response rate (RR), DCR, the median progression-free survival (PFS), and the median overall survival were 3.8%, 47.2%, 105 days, and 313 days, respectively. As for adverse events, allergic reactions to oxaliplatin (grade 1 or higher) occurred in 26% of the patients. RR, DCR, and PFS in 44 patients with the oxaliplatin-free-interval (OFI) over 6 months were 4.6%, 54.6%, and 119 days, respectively, and were statistically better than those in 9 patients with OFI less than 6 months (0%, 11.1%, and 84 days). Reintroduction of oxaliplatin with bevacizumab showed better PFS than that without bevacizumab (114 days and 78 days, respectively). Conclusions: Reintroduction of oxaliplatin was suggested to be one option for the management of colorectal cancer that is resistant to standard therapy, especially in patients with OFI over 6 months. Bevacizumab may enhance the results of reintroduction treatment.
Patterns of systemic therapy in metastatic colorectal cancer (mCRC): Use of intermittent and stop-and-go strategies in a population-based setting.
Authors: Cheung Winson Y. , Lim Howard John , Renouf Daniel John
Published: February 2017

644

Background: The concept of treatment to disease progression must be tempered by the potential for cumulative toxicities of ongoing therapy. Data suggest that treatment holidays may provide improved quality of life without significantly compromising outcomes in metastatic disease. Our aim was to characterize the frequency of intermittent and stop-and-go strategies in a population-based cohort of mCRC patients. Methods: Patients diagnosed with mCRC and who received any palliative systemic treatment at the British Columbia Cancer Agency from Jan 2008 to Dec 2010 were identified from the provincial pharmacy database. First-line (1L) and second-line (2L) therapy choices, duration on each line of therapy, and number of treatment holidays, defined as any time interval of >/= 4 weeks without any therapy, were characterized. Results: In total, 946 patients were identified: median age was 64 (IQR 55-72) years, 521 (55%) were men, and 626 (66%) had colon cancer. In 1L treatment, the majority received combination systemic therapy: 474 (50%) FOLFIRI +/- bevacizumab (B), 224 (24%) FOLFOX +/- B, and 248 (26%) 5-FU/capecitabine. The median number of cycles on 1L therapy was 9 (IQR 4-13). Treatment holidays were common with 302 (32%) patients experiencing at least one break, each lasting a median of 49 (IQR 36-99) days. Compared with no B, 1L patients treated with B received more therapy (median 12 [IQR 8-20] vs 8 [IQR 4-12] cycles). However, they were also more likely to undergo a treatment holiday (34% vs 31%), but the duration of each break was shorter (median 49 [IQR 36-92] vs 56 [IQR 35-119] days). Only 312 (33%) out of the 946 patients proceeded to 2L therapy. The median interval between stopping 1L and starting 2L was 43 (IQR 20-162) days. Compared with 1L, the median number of treatment cycles was shorter in 2L (median 7 [IQR 4-12]). Treatment holidays were also less frequent with only 50 (16%) out of 312 patients experiencing at least one break, each lasting a median of 56 (IQR 38-100) days. Conclusions: The use of the stop-and-go approach was prevalent in this population-based cohort of mCRC patients. The relationship between intermittent treatment and outcomes will be presented at the meeting.
Outcomes after radiation therapy for brain metastases from gastrointestinal primaries.
Authors: Unger Keith Robert , Collins Brian Timothy , Marshall John , Pishvaian Michael J. , He Ruth , Collins Sean P.
Published: February 2017

647

Background: There is limited data regarding outcomes of patients with colorectal cancer (CRC) and other gastrointestinal (GI) cancers metastatic to the brain. The aim of this study is assess intracranial disease control in GI patients treated with radiation therapy (RT) and the likelihood of receiving systemic therapy following the diagnosis of metastatic disease to the brain. Methods: From 1/2007 to 6/2013, 24 consecutive patients with adenocarcinoma of a GI primary were treated with RT for brain metastases. Patients were excluded if they had prior RT to the brain. The majority of patients had CRC (n = 15). Ten patients had resection of at least one brain tumor prior to radiation therapy. Patients were treated with the following RT modalities: stereotactic radiosurgery alone (n = 12), whole brain RT (n = 7), both (n = 1), and partial brain RT (n = 1). Survival and control rates were analyzed by the Kaplan-Meier method. Results: Twenty-one patients had died at the time of analysis and the median overall survival was 5.4 months (range, 0.5 – 58 months). Radiographic follow up was available in 20 patients and 60% (12/20) had intracranial disease progression. The 6- and 12-month control rates for the treated tumors were 60% and 30%, respectively. Seven patients received salvage radiation therapy following intracranial disease progression. Fifty-eight percent (14/24) did not receive further systemic therapy. On univariate analysis, only prior surgical resection predicted for improved survival (3.8 vs. 7.8 months, p = 0.018), while number of lesions, performance status, primary site, chemotherapy after RT, and RT modality were not significant. Conclusions: Survival and intracranial disease control following RT for brain metastasis from GI cancers are poor and many patients do not receive further systemic therapy. In this small series, outcomes are worse than published series for other disease sites metastatic to the brain and further research is warranted.
Effect of previous abdominal surgery on short-term outcomes following laparoscopic colorectal surgery.
Authors: Hotchi Masanori , Waki Yuhei , Tokuda Kazunori , Obatake Masayoshi , Kotegawa Hiroshi , Yoshiyama Hirotsugu , Harada Masamitsu , Kawasaki Hideki
Published: February 2017

653

Background: The impact of previous abdominal surgeries on the need for conversion to open surgery and on short-term outcomes during/after laparoscopic colorectal surgery was retrospectively investigated. This retrospective cohort study was conducted from May 2004 through October 2012. This study was conducted at Tokushima University Hospital and Ehime Prefectural Central Hospital. Methods: A total of 145 consecutive patients who had undergone laparoscopic resection of the sigmoid colon and upper rectum were classified as not having previous abdominal surgery (NPAS group, n = 123) or as having previous abdominal surgery (PAS group, n = 22). Short-term outcomes were assessed between the two groups. Results: The population of previous abdominal surgery consisted of 6 appendectomy, 3 gastrectomy for gastric ulcer, 2 nephrectomy, 2 peritonitis and 11 others (2 duplication). There were no significant differences in age, gender, BMI, tumor location, tumor size, Stage, operating time, blood loss and number of lymph node harvest between the two groups. The conversion to open surgery was performed in 1 patient (4.5%) in the PAS group and 6 patients (4.9%) in the NPAS group. The intraoperative inadvertent enterotomy occurred in 1 patient in the NPAS group. There was no difference in postoperative morbility between the two groups. In the NPAS group, anastomotic leakage was observed in 3 cases. Ileus was observed in one case in the NPAS and none in the PAS. Postoperative hospital stay was 14 days in the PAS group and 16 days in the NPAS group. Conclusions: Short-term outcomes following laparoscopic surgery for sigmoid colon and upper rectal cancer with previous abdominal surgery are acceptable.
Comparative analysis of uptake for 18F-fluorodeoxyglucose (FDG) versus 18F-fluorodeoxythymidine (FLT) PET scans in rectal cancer.
Authors: Sheybani Arshin , Bhatia Sudershan , Menda Yusuf , Boles-Ponto Laura , Gross Brandie Ann , Rockey William , McGuire Sarah Marie
Published: February 2017

657

Background: FLT PET is a novel metabolite for imaging cellular proliferation and has shown promise for treatment response monitoring. The utility of FLT PET imaging in rectal adenocarcinomas (RA) has not previously been established. We set out to compare FDG and FLT uptake in RA and correlate FLT response during treatment to tumor regression. Methods: We evaluated 6 patients with RA who were treated on an institutional prospective clinical trial (NCT01717391). Patients were treated neoadjuvantly with concurrent chemoradiation therapy per standard of care. Patients had both FDG and FLT PET scans prior to starting treatment and FLT scans after 1 and 2 weeks of radiotherapy. Tumor volumes and pelvic lymph nodes measuring greater than 6 mm were contoured on the simulation CT scan and adjusted for bladder and rectal filling based on the attenuation correction CT for each PET scan. FLT and FDG SUVs were collected from a total of 40 lymph nodes among the six patients. Pretreatment and change in tumor FLT SUVs were correlated with histopathological regression. The sensitivity of FLT and FDG for identifying lymph nodes was compared using a Student’s t-test. Results: At the time of this analysis, there were post-treatment pathological data on five patients. All but one patient had a decline in the FLT tumor SUV after 2 weeks of treatment. This non-responder was the only patient who did not have histopathological tumor regression after treatment and was the only patient whose pretreatment FLT SUV was below 2. Tumor FDG SUV (4.54 ± 1.03) was consistently higher compared to FLT (2.42 ± 0.51) values, however nodal uptake for FDG (1.89 ± 1.08) was not higher compared to FLT (1.98 ± 0.96). To account for this difference, nodal uptake was normalized to the SUV of each patient’s primary tumor for both FLT and FDG. Mean normalized lymph node FLT SUVs were significantly higher (0.80 ± 0.36) than normalized FDG SUVs (0.44 ± 0.25) (p<0.001). Conclusions: Preliminary data supports using FLT SUV as a biomarker for tumor response early during treatment. Relative FLT uptake in nodal metastasis also appears to be higher when compared to FDG. This indicates potential response and diagnostic applications for FLT PET imaging in RA Clinical trial information: NCT01717391.
The implementation of Lean Six Sigma methodology in a multidisciplinary outpatient clinic for gastrointestinal cancer.
Authors: Basta Yara , Monster Matthijs , Rohof Thomas , Tytgat Kristien M. A. J. , Klinkenbijl Jean H. G.
Published: February 2017

659

Background: In order to reduce long waiting times, a one-stop fast-track multidisciplinary outpatient clinic for gastrointestinal malignancies was initiated. Lean Six Sigma (LSS) is a combination of Lean-management and the Six Sigma methodology. LSS incorporates means to systematically identify and address suboptimal performance of a process. Lean and Six Sigma have their origin in the manufacturing industry, like the Toyota car factory, with largely homogenous products. In contrast, a complex high care oncology facility deals with heterogeneous patients. Our aim is to use the tools and strategies of LSS to increase the number of patients with an admission time (AT) of five days or less to ≥ 85% and to ensure that ≥ 90% of referring physicians receive the decisions formulated at the Multidisciplinary Team Meeting (MDTM) within one day. Methods: We have applied the DMAIC-cycle (Define, Measure, Analyse, Improve and Control) to our processes. The DMAIC-cycle is the management cycle of Lean Six Sigma. Results were measured before implementation of LSS and after for at least one month. Results: After implementing LSS causes for lags in AT, as well as for sending the documented decisions were identified. The lags in AT included patient delay, incomplete referral, official holidays and absences due to medical conferences. After the obstacles were successfully addressed we increased the percentage of patients with an AT ≤ 5 days from 48% to 70%, a 45% improvement. Causes for lags in sending the decisions, included verifying and signing the missive. Currently 99% of referring physicians receive the decision formulated by the MDT in ≤ 1 day. This is a substantial improvement from 2% to 99%. Conclusions: Lean Six Sigma is applicable in a multidisciplinary high care medical facility. Obstacles in the logistics of a complex medical facility can be identified and greatly improved.
Comparison of cetuximab (Cmab) with panitumumab (Pmab) monotherapy in salvage line against KRAS wild-type patients with metastatic colorectal cancer (mCRC): Analysis of HGCSG0901 and 1002.
Authors: Ueda Akira , Yuki Satoshi , Sasaki Takahide , Kobayashi Yoshimitsu , Hosokawa Ayumu , Doi Ayako , Tsuji Yasushi , Okuda Hiroyuki , Kato Takashi , Watanabe Yutaka , Miyagishima Takuto , Eto Kazunori , Ohta Tomoyuki , Takahata Takenori , Ikeda Shinichiro , Nakatsumi Hiroshi , Iwai Kazuhiro , Kato Kanji , Sakata Yuh , Komatsu Yoshito
Published: February 2017

663

Background: Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) such as Cmab and Pmab have antitumor activity and acceptable safety profiles in patients (pts) with mCRC. Monotherapy with Cmab or Pmab demonstrated the effectiveness in salvage-line, and the direct comparison was reported in ESMO 2013 (ASPECCT trial). Methods: Data of 31 pts with mCRC treated by monotherapy with Cmab (HGCSG0901) and 51 pts by monotherapy with Pmab (HGCSG1002) registered from 27 institutions in Japan. Comparison of Cmab with Pmab was retrospectively analyzed. All patients with KRAS wild type were refractory to or intolerant for 5-FU/irinotecan/oxaliplatin and also were never administered anti-EGFR-antibodies. Survival analyses were performed with Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Results: Patient characteristics were as below (Cmab vs. Pmab); male/female 20/11 vs. 27/24, median age (range) 65(44-76) vs. 64(44-81), PS 0-1/2-3 21/10 vs. 46/5, number of metastatic organs 1-2/3- 22/9 vs. 25/16. Skin toxicity was common adverse events and was generally similar in two groups. MST was 8.4 months in the Cmab and 8.1 months in the Pmab (p = 0.32). PFS was 3.8 months in the Cmab, as compared with 3.1 months in the Pmab (p = 0.60); the corresponding response rate was 19.4% and 13.7% (p = 0.54). After adjusting other prognostic factors with Cox proportional hazard model, the administration of Cmab/Pmab made significant difference neither for OS (HR 0.939, 95% CI 0.783-1.128, p = 0.503), nor PFS (HR 0.972, 95% CI 0.823-1.148, p = 0.735). Conclusions: In this integration analysis of two studies, there were no significant difference in efficacy between Cmab and Pmab monotherapy in the salvage-line treatment of pts with mCRC.
The effects of H. pylori CagA on DNA amplification and protein expression status of the HER2 gene in gastric cancer.
Authors: Shim Jung Ho
Published: February 2017

67

Background: We investigated whether Cag A contributes to the DNA copy change and expression of the HER2 gene mRNA transcript and, consequently, affects HER2 protein expression to evaluate the significance of H. pylori Cag A and HER2 amplification in gastric cancer. Methods: We used the AGS gastric cancer and HFE-145 immortalized non-neoplastic gastric mucosa cell lines to investigate whether Cag A regulates DNA copy number and HER2 expression. We also confirmed the effects of Cag A on gastric cancer tissues. Immunohistochemistry with or without fluorescence in situ hybridization (FISH) was conducted to determine the level of HER2 protein expression based on the revised criteria in the HER2 test guidelines. Results: H. pylori CagA transfected AGS cells showed a significant increase in HER2 gene copy number and expression. In addition, Cag A expression was detected in 17 (56.7%) of 30 gastric cancer (GC) tissues, and eight (47%) showed HER2 DNA amplification of more than two-fold (P = 0.013). A positive correlation was observed among DNA copy number, the mRNA transcript, and HER2 gene protein expression (p < 0.05). HER2 overexpression was detected in 12 (40%) of 30 gastric cancers by Hoffman’s criteria. Conclusions: These results suggest that H. pylori CagA may induce overexpression of the HER2 gene protein by increasing HER2 DNA and mRNA copy number. To overcome the weakness of the current HER2 assessment criteria, we propose to test HER2 DNA copy number changes with immunohistochemistry, instead of FISH.
The effect of stress on efficacy of dendritic cell therapy for esophageal squamous cell carcinoma.
Authors: Akutsu Yasunori , Qin Wei , Murakami Kentaro , Hoshino Isamu , Hanari Naoyuki , Nishimori Takanori , Mori Mikito , Isozaki Yuka , Toyozumi Takeshi , Hu Xin , Suito HIroshi , Akanuma Naoki , Takahashi Masahiko , Matsubara Hisahiro
Published: February 2017

69

Background: Recently, abscopal effect, by which systemic anti-tumor effect by local radiation therapy (RT) was elicited, has been reported. This phenomenon was thought to be mediated by stress protein gp96, a key molecule in antigen-presenting. We tested the enhancement of dendritic cell (DC) therapy by various stress, such as radiation or modulated electro-hyperthermia (mEHT) in DC therapy for squamous cell carcinoma (SCC). Methods: Mouse SCC cells, SCCVII, were inoculated into the left femur (primary tumor) of C3H/He mice subcutaneously, and also similarly inoculated into non-treated chest subcutaneous tissue (secondary tumor). Only the primary tumor was exposed to 4 or 10 Gy of RT or 5-10 watts of mEHT. Then DCs was injected only into the primary tumor. Following that, tumor volumes of the primary and secondary tumor were measured. Next, the population of immune-related T-cells in tumor-draining lymph nodes (TDLN) and gp96 expression in the primary tumor were evaluated. Results: With intratumoral injection of DCs and RT, primary tumor growth was markedly suppressed. Furthermore, secondary tumor growth was also suppressed. On the other hand, the combination of DCs and mEHT could inhibit tumor growth at both the primary and the secondary tumor. As for the population of T-cells, the population of CD3+, CD 4+ and CD 8+T-cells in the TDLN was markedly elevated and that of FoxP3 was reduced my mEHT. Gp96 expression, a stress protein, was strongly enhanced after RT and mEHT. Conclusions: Stress, such as RT or hyperthermia can enhance the efficacy of DC therapy and can induce a strong antitumor effect by stimulating the expression of stress protein, gp96. These combination therapies can be a strong systemic immunotherapy for esophageal SCC.
Expression relationships among EGFR family members and c-Met in esophagogastric adenocarcinoma.
Authors: Chan Ellie , Alkhasawneh Ahmad , Duckworth Lizette Vila , Zuluaga Toro Tania , Lu Xiaomin , Hughes Steven J. , George Thomas J.
Published: February 2017

75

Background: The incidence of esophagogastric adenocarcinoma is on the rise. The only targeted therapy that improves patient outcomes is the anti-HER2 antibody, trastuzumab; however, benefit is limited to cases with HER2 overexpression. Inhibition of EGFR in EGA is unsuccessful. cMet overexpression is a proposed resistance pathway for EGFR family inhibition. We sought to characterize the co-expression relationships among the EGFR family and cMet to identify potential dual therapeutic targets. Methods: This study included all sequential patients (pts) with adenocarcinoma of the esophagus and GEJ who underwent primary resection between 2001 to 2011 without neoadjuvant therapy or HER2 inhibition. Demographics, risk factors, tumor features, and outcome data were analyzed. Central blinded immunohistochemistry (IHC) was performed on FFPE tumor specimens with EGFR, HER2, HER3, HER4 and cMet expression scored as low/negative or high/positive expression. Descriptive statistics, Exact chi square test and Cox regression model were used for statistical analyses. Results: 48 pts (39 M/9 F) were eligible (median age 66yr; 37-83). Most (63%) were stage I (T1N0) and 93% had underlying Barrett’s esophagus. High expression of EGFR, HER2, HER3, HER4 and cMet were present in 70%, 43%, 77%, 38% and 56% of tumors respectively. HER3 and HER4 were commonly co-expressed (p=0.003) and moderately differentiated tumors had high expression of HER3 (p=0.01). Stage was the only variable that correlated significantly with survival (p=0.007). Conclusions: This study demonstrated that static baseline cMET expression levels are not associated with EGFR family expression profiles, although HER3/HER4 co-expression is common. No receptors demonstrated prognostic value. Further investigation into dynamic cMET expression changes related to active EGFR inhibition including prognostic and predictive value is warranted.
Prognostic stratification in esophagogastric adenocarcinoma in the revised AJCC staging (7th edition).
Authors: Zahoor Haris , Luketich James D. , Weksler Benny , Winger Dan G. , Christie Neil A. , Levy Ryan M. , Gibson Michael K. , Nason Katie S.
Published: February 2017

92

Background: AJCC esophageal staging assigns prognostic groups based on tumor, node, and metastasis classifications. In 2010, AJCC 7th ed. separated adenocarcinoma from squamous cell histology and added tumor grade and number of involved regional nodes. Our study aim was to compare survival prognostication for esophagogastric adenocarcinoma between AJCC 7 and AJCC 6thed. stage groupings. Methods: We abstracted pathology and survival for surgically-resected esophagogastric adenocarcinoma patients (n=836; 1997 to 2011); 256 received induction therapy. AJCC stage was assigned; overall survival in months (esophagectomy to death or most recent alive contact) was analyzed. Discriminatory ability and homogeneity, by stage, was assessed with Kaplan-Meier (KM) curves. Monotonicity comparisons were evaluated with linear trend chi-squared tests. Overall survival was compared using Cox regression and Akaike Information Criterion (AIC) was used to assess model fit. Results: Compared to AJCC 6, AJCC 7 restaged 165 patients. (Table) KM log-rank statistic indicated stronger differentiation in AJCC 7 curves compared to AJCC 6 (166.128 vs 185.523 overall). Cox likelihood ratio (162.957 vs. 173.951 overall) and AIC (4,831.011 vs 4,820.016 overall) indicated better model fit to the survival data for AJCC 7 versus AJCC 6, overall and for induction subgroups (data not shown). As stage group increases, stronger linear trends for survival were observed at 24, 36 and 60 months using AJCC7 stage groupings, overall and for induction subgroups, compared to AJCC 6. Conclusions: AJCC 7 stage groupings demonstrate superior homogeneity, discriminatory ability and monotonicity compared to AJCC 6. Incorporating the extent of nodal disease, and tumor grade into the revised AJCC 7 stage classification improves prognostic stratification of surgically resected esophagogastric adenocarcinoma patients, including patients who received induction therapy. [Table: see text]
Relationship of initial quality-of-life deficit and survival in esophageal cancer (EC): The Mayo Clinic Romero Registry experience.
Authors: Anderson Bradley W. , Sio Terence Tai Weng , Liu Heshan , Ginos Brenda F. , Romero Yvonne , Jatoi Aminah , Deschamps Claude , Sloan Jeff A. , Miller Robert Clell
Published: February 2017

97

Background: A diagnosis of EC significantly impairs patient (pt)’s survival and quality of life (QoL). We explored the relationship between pt-assessed QoL and survival. Methods: The Mayo Clinic Romero (formerly Esophageal Adenocarcinoma-Barrett's Esophagus) Registry prospectively collects clinical data during a pt's treatment course. QoL is recorded at enrollment (baseline) and annually using a validated 12-item Linear Analog Self-Assessment (LASA). A 10-pt scale is applied; ≤5 was termed clinically deficient QoL. Initial TNM staging, clinical (age, sex, prior chemotherapy, and esophagectomy), and socioeconomic variables (marital/employment status) were analyzed using Cox proportional hazards regression models. Results: 836 pts were analyzed. Median age was 64 years. 166, 506 and 164 pts had early, locally advanced, and metastatic EC, with 5-year survival rates of 75.1%, 33.6%, and 8.1%, respectively (P≤.0001). Poorer survival rates were seen in clinically QoL deficient pts in the following categories: Overall QoL (Hazard Ratio [H.R.] 0.66; 95% C.I., 0.54-0.80; P≤.0001) and LASA subsets for physical (H.R. 0.68; 95% C.I., 0.57-0.82; P≤.0001), emotional well-being (H.R. 0.69; C.I., 0.57-0.84; P=.0003), and social activity (H.R. 0.76; C.I., 0.63-0.91; P=.0028). No difference in survival was observed for marital or employment status, familial support, and financial/legal concerns. Pts with esophagectomy prior to LASA evaluation had improved survival (H.R. 0.68; 95% C.I., 0.55-0.85; P=.0005). No survival difference was observed whether pts received chemotherapy, before or after their baseline LASA evaluation. Conclusions: A strong association exists between pt’s overall survival and better overall QOL, physical, emotional well-being, and social activities. Using LASA to clinically monitor QoL at specified intervals may afford providers the opportunity to intervene when patients begin to experience QoL decline. The determinants of clinically deficit QoL and its impact on survival warrant further translational and prospective research.
RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE).
Authors: Wilke Hansjochen , Van Cutsem Eric , Oh Sang Cheul , Bodoky Gyorgy , Shimada Yasuhiro , Hironaka Shuichi , Sugimoto Naotoshi , Lipatov Oleg N. , Kim Tae-You , Cunningham David , Ohtsu Atsushi , Rougier Philippe , Emig Michael , Carlesi Roberto , Chandrawansa Kumari , Muro Kei
Published: February 2017

LBA7

Background: RAM is a human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We conducted a global, placebo-controlled, double-blind, phase III trial to evaluate the efficacy and safety of PTX +/- RAM in patients with metastatic GEJ or gastric adenocarcinoma who had disease progression on or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Methods: Pts received RAM (8 mg/kg IV q2w) or placebo (PL) plus PTX (80 mg/m2 d1, 8, 15 of a 4 week cycle) until disease progression, unacceptable toxicity, or death. Eligible pts had ECOG PS ≤ 1; and adequate organ function. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to progression (TTP), and safety. Results: From Dec 2010 to Sep 2012, 665 pts were randomized (RAM+PTX: 330; PTX: 335). Baseline characteristics were generally balanced between arms. The OS hazard ratio (HR) was 0.807 (95% CI 0.678, 0.962; p=0.0169). Median OS was 9.63m for RAM+PTX and 7.36m for PTX. The HR for PFS was 0.635 (95% CI 0.536, 0.752; p <0.0001). Median PFS was 4.40m and 2.86m. Median TTP was 5.5m RAM+PTX; 3.0m PTX (p <0.0001). ORR was 28% RAM+PTX;16% PTX (p=0.0001). Grade ≥ 3 adverse events (AEs) occurring in >5% of patients on RAM+PTX were: neutropenia (40.7% RAM+PTX;18.8% PTX), leukopenia (17.4% vs 6.7% ), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported in 3.1% RAM+PTX; 2.4% PTX. Conclusions: The primary endpoint of improved OS was met. A statistically significant and clinically meaningful OS benefit of > 2 months was observed for RAM+PTX vs. PTX in gastric and GEJ cancer after progression on 1st-line therapy, as were significant benefits in PFS and ORR. Neutropenia was more frequently reported in the RAM+PTX arm but incidence of febrile neutropenia was comparable between arms. Clinical trial information: NCT01170663.
Validation of a genomic classifier for predicting biochemical failure following postoperative radiation therapy in high-risk prostate cancer.
Authors: Den Robert Benjamin , Feng Felix Yi-Chung , Showalter Timothy Norman , Mishra Mark Vikas , Trabulsi Edouard John , Lallas Costas D. , Gomella Leonard G. , Birbe Ruth C. , McCue Peter , Ghadessi Mercedeh , Knudsen Karen E. , Dicker Adam
Published: February 2017

10

Background: Radiation therapy (RT) is commonly offered in the post radical prostatectomy (RP) setting, however response varies. We hypothesized that the genomic classifier ([GC] Decipher) score would predict biochemical failure (BF) and distant metastasis (DM) in men receiving post−RP RT. Methods: Under an institutional review board approved protocol, 223 men who underwent post−RP RT at the Kimmel Cancer Center of Thomas Jefferson University for pT3 or margin positive disease from 1990 to 2009 were identified. RNA was extracted from 143 patients with paraffin−embedded specimens and expression quantified from the highest Gleason grade tumor focus using a high−density oligonucleotide microarray. Excluding men who received neo−adjuvant therapy, 139 patients remained for GC calculation. Area under the receiver operating curve (AUC), decision curves, cumulative incidence accounting for competing risks, and multivariable Cox regression analyses were used to assess GC for predicting BF and DM after RT in comparison to nomograms. Results: The AUC of CAPRA-S was 0.67 (95% CI 0.58−0.77) and 0.65 (95% CI 0.44−0.86) for BF and DM, respectively. Integration of GC improved AUC to 0.75 (95% CI 0.66−0.84) and 0.77 (95% CI 0.64−0.91) for BF and DM, respectively. Cumulative incidence of BF at 8 years post-RT was 21%, 48%, and 81% for low (less than 0.4), intermediate (0.4 to 0.6), and high (more than 0.6) GC, respectively (p<0.00001). In multivariable analysis, patients who received RT early (pre−RT prostate-specific antigen [PSA] less than 1 ng/mL) had a BF benefit with a significantly reduced hazard ratio (HR) of 0.32 (95% CI 0.11−0.96, p<0.042). Patients with high GC had an HR of 14.73 for BF (95% CI 4.90−44.31, p<0.00001). Earlier PSA recurrence was observed in patients with high GC score that received salvage compared to adjuvant RT with median BF survival post-RT of 4.67 versus 8.78 years (p<0.04). This held true after adjusting for CAPRA-S score. Conclusions: This is the first validation of the GC in the post−RP RT setting. GC improved risk stratification above clinical classifiers. Patients with high GC received significant benefit from early RT intervention. For those patients with high pre-RT PSA and high GC, exploration of intensified therapy is warranted.
Cohort compassionate-use program (CUP) and early access program (EAP) with cabazitaxel (Cbz) plus prednisone (P; Cbz + P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D): Analysis by age group.
Authors: Malik Zafar , di Lorenzo Giuseppe , Bracarda Sergio , Ardavanis Alexandros , Basaran Mert , Parente Phillip , de Schultz Wito , Saad Fred , van Oort Inge , Gerritsen Winald R. , Antón Aparicio Luis M. , Matus Geoffrey , Hitier Simon , Heidenreich Axel , Bahl Amit
Published: February 2017

109

Background: Cbz + P demonstrated an overall survival benefit vs mitoxantrone + P in pts with mCRPC in the Phase III TROPIC trial. The CUP (CABAZ_C_05005) and EAP (NCT01254279) (both funded by Sanofi) were established to allow access to Cbz ahead of commercial availability. The programs are also evaluating Cbz safety in a real-world population. Data analyzed by age group (≤75 and >75 years) are presented here. Methods: Expected enrolment across both programs is 1,450 pts from 236 centres worldwide. Pts received Cbz 25 mg/m2 IV Q3W + P 10 mg QD until disease progression, death, unacceptable toxicity or physician/pt decision. G-CSF is administered as per ASCO guidelines. Results: As of May 30, 2012, 1,301 pts have enrolled (≤75 years: 1,061 pts [81.6%]; >75 years: 240 pts [18.4%]). Eastern Cooperative Oncology Group performance status and incidence of visceral metastases were generally balanced between treatment groups. The most frequent reasons for discontinuation were disease progression (46.8%) followed by adverse events (AEs; 24.4%) in pts ≤75 years, and AEs (36.4%) followed by disease progression (31.1%) in pts >75 years. Time from initial diagnosis to inclusion was greater in pts >75 years (median 79.66 months) than in pts ≤75 years (median 53.94 months), but time from mCRPC diagnosis to inclusion was approximately equivalent (>75 years: median 22.6 months; ≤75 years: median 20.94 months). G-CSF use was more frequent in pts >75 years (cycle 1: 62.9% of pts) compared with pts ≤75 years (cycle 1: 52.2% of pts). AEs of clinical concern were more frequent in the older age group (Grade ≥3 AEs: >75 years 64.2%; ≤75 years 54.8%). Grade ≥3 neutropenia was observed in 25.8% of pts >75 years and in 17.0% of pts ≤75 years. Conclusions: We observed several differences between age groups in baseline and on-treatment parameters, suggesting differences in the natural history of mCRPC (faster disease progression in pts ≤75 years than in pts >75 years) and secondary to treatment (AEs more frequent in pts >75 years compared with pts ≤75 years). Clinical trial information: NCT01254279.
Is clinical stage T2C prostate cancer intermediate- or high-risk disease?
Authors: Klaassen Zachary , Singh Abhay A , Howard Lauren , Terris Martha K. , Aronson William J , Cooperberg Matthew R. , Amling Christopher L , Kane Christopher J , Banez Lionel Lloyds , Freedland Stephen J.
Published: February 2017

110

Background: Clinical stage T2c (cT2c) is an indeterminate factor in the algorithm for prostate cancer (CaP) risk stratification. According to the D’Amico risk stratification and the American Urological Association (AUA) guidelines, cT2c is high−risk, whereas the National Comprehensive Cancer Network (NCCN) and EUA classify cT2c as intermediate−risk. Since determining whether cT2c is intermediate- or high-risk has implications for treatment, it is important to define what exact risk cT2c portends. Thus, we sought to assess whether cT2c tumors, without associated other high−risk factors (cT2c not otherwise specified (cT2c−nos)), behave as intermediate− or high−risk by analyzing biochemical recurrence (BCR) after radical prostatectomy (RP). Methods: We retrospectively analyzed 2,759 men who underwent RP from 1988 to 2011 from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Comparisons in time to BCR between cT2c−nos patients and intermediate−risk (prostate-specific antigen [PSA] 10 to 20 ng/ml or Gleason sum (GS) =7 or cT2b), and high−risk (PSA greater than 20 ng/ml, GS 8 to 10, cT3) patients was performed using log−rank test and Cox proportional hazards analyses. Given changes in CaP, we adjusted for year of surgery (continuous) and to adjust for case mix among centers contributing to SEARCH we included a categorical term for center. Results: A total of 99 men (4%) were classified as cT2c−nos. During a median follow-up of 66 months (IQR: 34−101 months), cT2c−nos patients had similar BCR risk as intermediate-risk (p=0.27), but significantly lower BCR risk versus high-risk patients (p<0.001, Figure). After adjusting for year and center and compared to low-risk disease, the HRs for cT2c−nos patients was similar to those with intermediate-risk (HR 1.90 vs. 2.28). When specifically compared to intermediate-and high-risk patients, and after adjusting for year and center, cT2c−nos patients had outcomes comparable to intermediate−risk (p=0.44), but significantly better than high-risk patients (HR 0.55; 95%CI 0.38,0.78; p=0.001). Conclusions: BCR risk for patients with clinical stage T2c was comparable to men who had intermediate-risk disease and significantly better than men with high-risk CaP. These findings suggest men with cT2c disease should be offered treatment options for intermediate-risk CaP.