bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of PI3K/p-AKT/p-mTOR in gastric carcinoma and its correlation with clinicopathologic characteristics.
Authors: Jieer Ying , Qi Xu , Bixia Liu , Xiangdong Cheng
Published: February 2017

73

Background: The objective of this study was to explore the expression patterns of PI3K/p-AKT/p-mTOR in gastric cancer (GC) and its relationship with clinicopathological characteristics and thereby to understand the role of activated PI3K/AKT/mTOR pathway in the initiation and development of gastric cancer. Methods: Envision immunohistochemistry assay was used to examine the expression patterns of PI3K, p-AKT and p-mTOR in primary GC sites, metastatic lymph nodes and peritumoral mucosa among 50 patients who underwent radical gastrectomy for stage I-IV (M0) gastric cancer. Results: The PI3K, p-AKT and p-mTOR showed significantly higher expressions in primary tumor sites and metastatic lymph nodes as compared to that of the peritumoral mucosa. The study of the pathway components and clinicopathological characteristics revealed that p-AKT and p-mTOR expressions were selectively higher in primary tumors with less than 5 cm diameter. The PI3K, p-AKT and p-mTOR positive patients had shorter median survival time as compared to the patients negative for them (42.8 m vs. 57.0 m, 46.8 m vs. 55.9 m, 47.2 m vs. 53.0 m). However, the differences were not statistically significant. Conclusions: Activation of PI3K/AKT/mTOR pathway was associated with the development and prognosis of gastric cancer. The expression of PI3K/p-AKT/p-mTOR was correlated well with tumor specificity in gastric cancer and they might have some potential as promising targets for clinical therapy.
Role of aurora kinase A on regulating inflammation and inducing NF-κB pathway activation in gastric cancer.
Authors: Katsha Ahmed M. , Sehdev Vikas , Soutto Mohammed , Peng DunFa , Belkhiri Abbes , El-Rifai Wael
Published: February 2017

78

Background: Aurora kinase A gene (AURKA) is frequently amplified and/or overexpressed in several malignancies. Inflammation contributes to the pathogenesis of gastric tumorigenesis. We explored the roles of AURKA in inflammation and tumorigenesis. Methods: Immunofluorescence, immunohistochemistry, Quantitative real-time PCR, immunoblot, co-immunoprecipitation, luciferase reporter, and in vitro kinase assays were used to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1–/– mice, growth of tumor xenografts, and human tissues. Results: We showed an elevated level of AURKA in the Tff1–/– gastric tissues as compared to wild-type. We also found a positive correlation between AURKA and inflammation (coefficient r = 0.25; P = 0.0056) as well as TNF-α (coefficient r = 0.25; P = 0.0057). AURKA inhibition by MLN8237, a specific AURKA inhibitor, reduced nuclear staining of NFκB in human gastric cancer samples and mouse epithelial cells, suppressed NFκB reporter activity, and reduced the expression of NFκB target genes that regulate inflammation and cell survival. Additionally, AURKA inhibition reduced xenograft tumor size in mice and reversed the development of gastric tumors in Tff1–/– mice. Further, we found that AURKA regulate NFκB activity by directly binding and phosphorylating IκBα in vitro. Premalignant and malignant lesions from the gastric mucuosa of patients had increased levels of AURKA protein and nuclear NFκB, compared with healthy gastric tissue. Conclusions: In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be upregulated during chronic inflammation to promote IκBα-mediated activation of NFκB and tumorigenesis. This provides a novel role of AURKA in cancer and shows the importance of targeting it as a therapeutic approach in cancer treatment.
Effect of chemoradiotherapy, with adjuvant surgery for local control, on survival in AC and SCC of the esophagus.
Authors: Bass Gary Alan , Furlong Heidi , O'Sullivan Katie E. , Hennessy Thomas P.J. , Walsh Thomas Noel
Published: February 2017

81

Background: Esophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. Aims:Long-term results of 2 simultaneous RCTs comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of AC (AC) and SCC (SCC) to identical regimens compared. Methods: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately randomised to identical protocols of MMT or surgical monotherapy. Results: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0·004), SCC (P=0·01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery(64% vs 29%, P<0·001). MMT produced a pCR in 25% and 31% of AC and SCC respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR vs surgical monotherapy(P=0·001); residual disease following MMT vs surgical monotherapy(P=0·008);SCC pCR vs surgical monotherapy (P=0·033). Conclusions: A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumor down-staging to extinction in 25-31% of patients, potentially permitting personalized treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localized disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease.
Safety profile of thoracoscopic esophagectomy for esophageal cancer compared with traditional thoracotomy from the results of JCOG0502: A randomized trial of esophagectomy versus chemoradiotherapy.
Authors: Nozaki Isao , Kato Ken , Igaki Hiroyasu , Ito Yoshinori , Daiko Hiroyuki , Yano Masahiko , Udagawa Harushi , Nakagawa Satoru , Takagi Masakazu , Okabe Hiroshi , Abe Tetsuya , Nakamura Tetsu , Hihara Jun , Toh Yasushi , Akutsu Yasunori , Shibuya Yuichi , Mizusawa Junki , Nakamura Kenichi , Fukuda Haruhiko , Kitagawa Yuko
Published: February 2017

82

Background: Esophagectomy for esophageal cancer via the thoracoscopic approach (TA) is expected to reduce the extent of trauma compared with traditional thoracotomy (TT). However, there have been few prospective studies comparing perioperative complications between TA and TT after esophagectomy. Therefore, this study aimed to clarify whether TA is a safe procedure with regard to morbidity and mortality using the data of patients (pts) who underwent esophagectomy in the JCOG0502 trial. Methods: The JCOG0502 trial is a currently on-going randomized trial including a patient preference arm of esophagectomy versus chemoradiotherapy for treatment of clinical stage I esophageal cancer. The primary analysis of overall survival is planned in 2018. In this trial, thoracic squamous cell carcinoma, adenosquamous carcinoma, and basaloid carcinoma of stage T1b/N0/M0 were eligible. When pts were randomized to surgery or selected surgery, esophagectomy with D2–3 lymphadenectomy was performed. TA or TT was selected at the surgeon’s discretion. Perioperative complications were defined as adverse events of grade 2 or greater as per CTCAE v3.0. Results: A total of 379 pts (11 randomized and 368 in the patient preference arm) were enrolled between December 2006 and February 2013 from 37 institutions, and 211 pts underwent surgery. Of these 211 pts, TA was performed in 101 pts while TT was performed in 110 pts. Blood loss was less in the TA group than in the TT group (median, 293 vs. 410 mL, respectively), and the surgical duration was longer in the TA group than in the TT group (median, 510 vs. 398 min). The proportion of intraoperative complications was similarly low in both groups. However, postoperative anastomotic leakage, pneumonia, and atelectasis were less common in the TA group than in the TT group (7%, 8%, and 11% vs. 14%, 17%, and 22%). Moreover, the proportion of recurrent nerve palsy was similar among both groups (15% vs. 16%). Each group had one in-hospital death. Conclusions: This study indicated that TA did not increase morbidity or mortality after esophagectomy and can be safely performed with risks comparable to those with TT. Clinical trial information: UMIN000000551.
Phase II study of trastuzumab in combination with capecitabine and oxaliplatin in patients with advanced gastric cancer.
Authors: Ryu Min-Hee , Ryoo Baek-Yeol , Park Young Soo , Park Sook Ryun , Kim Jong Gwang , Han Hye-Suk , Chung Ik-Joo , Song Eun-Kee , Lee Kyung Hee , Kang Seok Yun , Kang Yoon-Koo
Published: February 2017

83

Background: Trastuzumab (Herceptin) in combination with capecitabine and cisplatin has been the standard first-line chemotherapy in patients with HER2-positive advanced gastric cancer (AGC). Oxaliplatin is generally less toxic and more convenient than cisplatin, and currently replacing cisplatin for the treatment of AGC. This study aims to investigate the efficacy and safety of trastuzumab in combination with capecitabine and oxaliplatin (HER-XELOX) in HER2-positive AGC. Methods: With Simon’s minimax two stage design (P0[response rate of historic control]=0.4, P1=0.55, two-sided alpha=0.1, beta=0.2, and 10% drop-out rate), a total of 55 patients with AGC positive for HER2 defined as either HER2 immunohistochemistry (IHC) 3+ or IHC 2+and FISH+ were enrolled from Aug 2011 to Feb 2013. HER-XELOX regimen consisted of trastuzumab 8 mg/kg i.v. on day 1 in cycle 1 and then 6 mg/kg in subsequent cycles, capectabine 2000 mg/m2/day p.o. on days 1-14, and oxaliplatin 130 mg/m2i.v. on day 1, every 3 weeks. HER-XELOX was administered as a first-line chemotherapy until disease progression, unacceptable toxicity, or consent withdrawal. Results: Among the 55 patients, 37 (66%) patients were male. Median age was 57 years (range, 29-74). ECOG performance status was 0-1 in 51 (93%) patients. Fifty three (96.4%) patients had metastatic disease, and 2 (3.6%) had locally advanced unresectable disease. With complete response in 2 patients and partial response in 35 patients, confirmed overall response rate was 67.3% (95% CI, 54-80%). With a median follow-up of 13.8 months (range, 6.1-23.9) in surviving patients, median progression-free survival was 9.8 months (95% CI, 7.0-12.6). Median overall survival was 21.0 months (95% CI, 6.4-35.7). Common grade 3 or 4 toxicities with frequency > 10% included neutropenia (18.2%), anemia (10.9%), and neuropathy (10.9%). There was no febrile neutropenia. One patient died of treatment-related diarrhea and sepsis. Conclusions: HER-XELOX regimen is well tolerated and highly effective in patients with HER2-positive AGC. Clinical trial information: NCT01396707.
Utilization of laparoscopy for resections of stomach and esophagus cancers: Is hospital the deciding factor?
Authors: Bliss Lindsay A. , Chau Zeling , Yang Catherine J. , Smith Jillian K. , Witkowski Elan R. , Ragulin-Coyne Elizaveta , Ng Sing Chau , Critchlow Jonathan F. , Moser Arthur J. , Tseng Jennifer F.
Published: February 2017

86

Background: Foregut surgery is technically complex. Outcomes for such high-stakes operations receive increasing scrutiny and the use of minimally invasive approaches has been further adopted. This study aims to determine national trends in laparoscopy utilization and patient outcomes for potentially curative cancer resections of the esophagus and stomach. Methods: Retrospective review of all esophageal and gastric cancer resections in the Nationwide Inpatient Sample during 1998 to 2011. Univariate analyses of sex, race, admission status, Elixhauser comorbidity score, year, insurance, hospital characteristics, procedure, and center volume were performed by chi-square. Cochran-Armitage test was used for trends. Logistic regressions were used to model inpatient mortality, complications and laparoscopy. Results: From 1998 to 2011, 120,527 and 25,540 patients (nationally-weighted records) underwent gastrectomies and esophagectomies for cancer. From early (1998-2002) to late (2008-2011) study years, inpatient mortality decreased from 6.69% to 3.88% (<0.0001) and complications increased from 27.41% to 31.63% (<0.0001) for gastrectomy. Similarly, inpatient mortality decreased from 9.75% to 5.53% (<0.0001) and complications increased from 37.69% to 43.07% (<0.0001) for esophagectomy. Use of laparoscopy in gastrectomy increased from 1.64% to 5.89% (p <0.0001) and in esophagectomy from 0.80% to 5.74% (<0.0001). Patients undergoing laparoscopy had lower inpatient mortality (3.13% vs. 5.96%, p=0.0010) and were less likely to experience complications (26.20% vs. 31.47%, p=0.0121). After adjustment, independent predictors of the use of laparoscopy included elective admission, female sex, resection after 2003 and resection at a large (vs. medium), urban, teaching high volume center (vs. low volume center) in the Northeast (vs. Midwest and South). Conclusions: Inpatient mortality and complications for gastrectomy and esophagectomy have improved over the past decade. Use of minimally invasive techniques is expanding with associated superior patient outcomes. Resection hospital characteristics drive which patients undergo laparoscopy for esophagus and stomach cancers.
A randomized phase III trial of second-line chemotherapy comparing CPT-11 alone versus S-1 plus CPT-11 combination therapy in advanced gastric cancer refractory to first-line therapy with S-1 (JACCRO GC-05).
Authors: Nishikawa Kazuhiro , Tanabe Kazuaki , Fujii Masashi , Kunisaki Chikara , Tsuji Akihito , Matsuhashi Nobuhisa , Takagane Akinori , Ohno Tetsuro , Kawase Tomono , Kochi Mitsugu , Yoshida Kazuhiro , Kakeji Yoshihiro , Ichikawa Wataru , Chin Keisho , Terashima Masanori , Takeuchi Masahiro , Nakajima Toshifusa
Published: February 2017

87

Background: In East Asia, S-1 + CDDP (SP) has been employed as first-line therapy for advanced gastric cancer (AGC) from the results of SPIRITS trial. Patients who were resistant to chemotherapy with S-1 in the first-line treatment were widely treated with taxane alone or CPT-11 alone as the second-line treatment. On the other hand, the response rate of combination therapy with S-1 is higher than that of CPT-11 alone. Then, we hypothesized that S-1 + CPT-11 prolongs survival in the second-line treatment comparing with CPT-11 alone after failure in the first-line treatment with S-1. (NCT00639327). Methods: Patients with AGC who confirmed disease progression by imaging after the first-line therapy with SP, S-1 + cocetaxel or S-1 alone except S-1 + CPT-11 were allocated into S-1 plus CPT-11 group (Group A) or CPT-11 alone group (Group B) as second-line chemotherapy. Patients who were relapsed to adjuvant chemotherapy with S-1 were not enrolled. Primary endpoint was overall survival, and secondary endpoints were progression free survival, response rate and adverse events. Results: From March 2008 to June 2011, 304 patients were enrolled, and 294 were eligible for analysis. The overall survival was 8.8 months (M) in the Group A and 9.4M in the Group B. There is no statistically significant difference in both groups (P=0.9156). The progression free survival was 4.8M in the Group A and 4.9M in the Group B (P=0.1568). The response rate was 7.6% in the Group A and 7.4% in the Group B. Grade 3 or higher leukopenia, neutropenia and febrile neutropenia were observed more frequently in the Group A than in the Group B. Conclusions: From our results, we do not recommend consecutive use of S-1 as second-line treatment in patients who are refractory to S-1 in first-line chemotherapy. Clinical trial information: 00639327.
ICORG 06-41: A phase II trial of single-agent sorafenib in the treatment of platinum-pretreated relapsed gastroesophageal adenocarcinoma (GECa).
Authors: Connell Louise Catherine , O'Reilly Seamus , Webb Glenn , Moulton Brian , Parker Imelda , McDermott Raymond , McCaffrey John , Grogan William , Leonard Gregory , Power Derek Gerard , Horgan Anne M. , Bird Brian , O'Byrne Kenneth John
Published: February 2017

88

Background: Over 1 million individuals worldwide annually are diagnosed with GECa. The majority of patients(pts) present with inoperable locally advanced or metastatic disease(dx). Even with resectable dx 5 year survival is low at ~40% with current best treatment (tx). Following initial platinum based therapy there is no established standard 2nd line tx. Besides HER2-directed therapy there has been little progress with targeted biologic agents. ICORG, the all-Ireland Cooperative Oncology Research Group investigated the utility of the tyrosine kinase inhibitor sorafenib in a multicentre trial. Methods: A prospective Phase II, nonrandomised, open label, one arm study of single agent sorafenib in the tx of platinum pre-treated relapsed GECa was conducted. Primary objective was dx control rate (DCR) post 4 months of tx. Secondary endpoints were OS, PFS, TTP, ORR, tolerability/toxicity and biomarkers of tx response/resistance. The protocol allowed for an interim analysis to be performed if clinically indicated. A sample size of 54 pts was identified using the single stage Fleming design approach to test whether the proportion responding, P, is ≤ 0.35 or ≥ 0.50. Pts received Sorafenib 400mg bid p.o. continuously q28days until dx progression or intolerable toxicity. Response by RECIST was evaluated by CT q8weeks. For pts with sufficient tumour samples translational studies were done. Results: An interim review performed in Nov 2012 (35 months post study opening) indicated that 33/41 evaluable pts recruited to date had progressed before completing 4 months of tx. Therefore, the number of evaluable pts with dx control could not reach the pre-specified figure of 22, & the hypothesis P >= 0.50 was rejected. Fifteen pts had just 1 cycle of tx, 5 of whom completed ≤ 2 weeks. A further 14 pts had 2 cycles. Median survival time to progression was 56 days (95% CI 53 – 59 days).Median OS was 120 days (95% CI 91 – 149 days). Safety data analyses and translational studies are ongoing and will be available for presentation at the meeting. Conclusions: Sorafenib as monotherapy is inactive in platinum pretreated pts with relapsed GECa. A significant unmet clinical need for novel effective therapies remains. Clinical trial information: 2008-005062-31.
Serum angiopoietin-like protein 2 as a novel biomarker of diagnosis and prognosis in gastric cancer.
Authors: Toiyama Yuji , Inoue Yasuhiro , Kitajima Takahito , Shimura Tadanobu , Imaoka Hiroki , Kondo Satoru , Ide Shozo , Okigami Masato , Yasuda Hiromi , Saigusa Susumu , Ohi Masaki , Tanaka Koji , Mohri Yasuhiko , Kusunoki Masato
Published: February 2017

9

Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein with homology to the angiopoietins and is known to act as a causative mediator of chronic inflammation and inflammatory carcinogenesis. Recently, we demonstrated that ANGPTL2 overexpresses in gastric cancer (GC) compared to normal gastric mucosa and high ANGPTL2 is associated with poor prognosis. Therefore, if tumor-derived ANGPTL2 over-secretes systemically, focusing ANGPTL2 in blood is logical to evaluate its ability as a biomarker. Accordingly, we quantified serum ANGPTL2 level and assessed its clinical significance in GC patients. Methods: We screened serum ANGPTL2 levels from 32 GC and 24 normal controls (NC) by ELISA (cohort 1). Next, we validated 194 serum samples from GC and 48 NC (cohort 2). Finally, we examined ANGPL2 expression in matched GC tissues of cohort 2 (n=194) by immunohistochemistry (IHC). The IHC score of ANGPTL2 was determined on the basis of both staining intensity and the percentage of positive cells. Results: In cohort 1,serum ANGPTL2 levels in GC were significantly higher than that in NC (p<0.05). Serum ANGPTL2 differentiated GC from NC with high accuracy (AUC=0.814). Analysis of cohort 2 also indicated that serum ANGPTL2 levels in GC were significantly higher compared to NC (p<0.0001), and increased according to UICC stage progression. In addition, serum ANGPTL2 had a promising AUC (0.831) with high sensitivity (73.0%) and specificity(82.2%) to distinguish GC from NC. High serum ANGPTL2 was significantly associated with lymphatic invasion (p=0.03), vessel invasion (p=0.02), distant metastases (p=0.0002), early recurrence (p=0.004) and poor survival (p=0.01), consequently emerged as an independent predicting recurrence marker (HR=5.06, p=0.0004) and prognostic marker (HR=3.6, p=0.01) in GC. Of interest, ANGPTL2 levels in serum from GC patients closely correlated with IHC scores of cytoplasmic ANGPTL2 at the invasive margin of matched GC tissues (r= 0.16, p=0.02). Conclusions: Serum ANGPTL2 levels, which might be secreted from primary or metastatic site into blood stream, have extremely strong potential as a novel biomarker for diagnosis, predicting recurrence and poor prognosis in GC patients.
FDG-PET scan after induction chemotherapy for esophageal squamous cell cancer (ESCC) to predict for outcomes after chemoradiation (chemoRT) and to guide salvage chemotherapy during RT.
Authors: Ku Geoffrey Yuyat , Janjigian Yelena Yuriy , Kriplani Anuja , Ong Leonard , Rusch Valerie W. , Bains Manjit S. , Rizk Nabil P. , Sarkaria Inderpal S. , Capanu Marinela , Goodman Karyn A. , Ilson David H.
Published: February 2017

94

Background: Pre-operative or definitive chemoRT is accepted treatment for locally advanced (LA) ESCC. We have retrospectively shown that assessment by PET scan following induction chemo prior to chemoRT and surgery predicts outcomes in SCC Pts (Cancer 118:2820; 2012). Some Pts with progression on PET after induction chemo had long-term survival when changed to alternative chemo during RT. Methods: We retrospectively reviewed all Pts with LA ESCC who received induction chemo and chemoRT from 2002 to 2010; all Pts had PET scan before and after induction chemo. Results: 62 Pts were identified, median age 63, median Karnofsky performance status 80%, 75% with uN+ disease. 43 (69%) received induction chemo with platinum/irinotecan (CPT-11), 13 (21%) with platinum/paclitaxel and 6 (10%) with docetaxel/CPT-11 ± cisplatin. 38 Pts (61%) were PET responders (PETr; ≥35% decrease in mSUV of tumor) and 24 (39%) were PET non-responders (PETnr; <35% decrease). All PETr received same chemo during RT. Of PETnr, 9 continued with same chemo during RT and 15 were changed to a different chemo with RT. 33/38 PETr (87%) achieved a clinical complete response (cCR) vs. 4/9 (44%) of PETnr/no chemo change vs. 11/15 (73%) of PETnr/chemo change (p=0.01 for PETr vs. PETnr/no chemo change; p=0.25 for PETr vs. PETnr/chemo change). 17 Pts had resection, all R0; 5/12 PETr (42%) had pathologic CR (pCR) while 0/3 PETnr/no chemo change Pts had pCR. Median disease-specific survival (not reached vs. 19 mos, p=0.002) and overall survival (OS; 69.6 vs. 17.4 mos, p=0.0056) were significantly better for PETr vs. PETnr. Median OS for PETnr/chemo change was 19.6 mos vs. 13.3 mos for PETnr/no chemo change (p=0.50); 6/15 PET nr who had different chemo with RT have extended survival, including 4 who are without disease at 2.8 – 9+ years. Conclusions: PET scan after induction chemo appears to predict for outcomes in ESCC Pts who received chemoRT. Long-term survival is possible in PETnr who switch to different chemo during RT. Such a strategy should be prospectively evaluated in a clinical trial.
Predictors of disease control in patients treated with platinum-based chemotherapies for metastatic squamous-cell esophageal cancer: First results of the e-DIS trial.
Authors: Adenis Antoine , Bennouna Jaafar , Galais Marie-Pierre , Tresch Emmanuelle , Francois Eric , Etienne Pierre-Luc , Ben Abdelghani Meher , Michel Pierre , Seitz Jean-François , Conroy Thierry , Ghiringhelli Francois , Bedenne Laurent , Samalin Emmanuelle , Piessen Guillaume , Hiret Sandrine , Peugniez Charlotte , Herin Helene , Clisant Stephanie , Kramar Andrew , Mariette Christophe
Published: February 2017

95

Background: There is little evidence that chemotherapy (CT) impacts on outcome of patients with MSEC. We designed an ongoing randomized phase 2 trial to detect a progression-free survival benefit of CT continuation over CT discontinuation in disease-controlled and ECOG≤2 patients at 6 weeks after an initial CT treatment. The aim of the present study was to identify predictors of disease control at 6 weeks (DC6wkx) in MSEC patients receiving platinum-based CTs as first-line treatment for metastatic disease. Methods: Among 68/70 evaluable patients included between 1/2011 and 7/2013 who received at least 1 CT cycle, 58 were evaluable for disease assessment at 6 weeks. Ten patients were not evaluable (early death: 4, patient’s decision: 2, concomitant disease 1, early progressive disease 1, other reasons: 2). Baseline demographic, clinical, biological, and tumor characteristics were tested for prediction of DC6wkx. Significant variables for DC6wkx were identified with the chi-squared test and logistic regression. Results: Baseline patients characteristics were as follows: median age: 61.5yo; male: 57/68; ECOG 0/1/2: 13/42/13; metachronous/synchronous MSEC: 38/30; number of metastatic sites 1/2/>2: 35/20/13; metastatic location: lung 36, liver 23, bone 11, nodes 37, other 11; prior exposure to CT: 37/68; time from previous CT exposure: ≤ 6m 6/37, 6-12m 14/37, > 12m 17/37; gr>2 dysphagia (Atkinson) 19/67; BMI<18.5kg/m²: 13/68. Current CTs were FU-CDDPq3w 2/68, LV5FU2-CDDPq2w 15/68, FOLFOX 51/68, and patients received the following number of cycles 1/2/>2: 5/7/54. DC6wkx rate was 65.7%, with 16/68 PR (23.5%) and 28/68 SD (42.2%). Albumin (p<0.01), BMI (p<0.02), bone metastases (p<0.005), gender (p<0.047) and ECOG status (p<0.05) were predictive of DC6wkx. Normal or overweight BMI, grade 0 albumin, and no bone metastases, were predictive of DC6wkx in multivariate analysis. Conclusions: DC at 6 wks was 65.7% in MSEC receiving platinum-based CTs as first line treatment for metastatic disease. Normal or overweight BMI, normal albumin, and the absence of bone metastasis were significant predictors of DC6wkx in this prospective phase 2 trial. Clinical trial information: NCT01248299.
Comparison of the long-term toxicities conferred by two different doses of definitive chemoradiotherapy for stage II/III esophageal squamous cell carcinoma.
Authors: Kubo Emi , Kato Ken , Okita Natsuko T. , Takashima Atsuo , Honma Yoshitaka , Iwasa Satoru , Hamaguchi Tetsuya , Yamada Yasuhide , Shimada Yasuhiro , Ito Yoshinori , Itami Jun
Published: February 2017

96

Background: Deﬁnitive chemoradiotherapy is one of the options for stage II/III esophagealsquamous cell carcinoma (ESCC). RTOG9405 recently reported that a higher dose of radiation did not confer any additional survival benefit over the standard dose (50.4 Gy). We comparedthe long-term toxicities conferred by chemoradiation at a dose of 60 Gy and 50.4 Gy for stage II/III ESCC. Methods: Eligibility criteria included clinical stage II/III (non-T4) (UICC-TNM, 6th edition) ESCC, performance status 0-2, and age 20-75 years. The study group comprised 254 patients who received definitive chemoradiotherapy as first-line therapy between January 2000 and August 2010 in our hospital. Group J (n=207) received 2 cycles of cisplatin (40 mg/m2 on days 1 and 8) with fluorouracil infusion (400 mg/m2/day on days 1-5 and 8-12), or 2 cycles of cisplatin(70 mg/m2 on day 1) with fluorouracil infusion (700 mg/m2/day on days 1-4) and concurrent radiotherapy at 60 Gy. Group R (n = 47) received 2 cycles of cisplatin (75 mg/m2 on day 1) with fluorouracil infusion (1000 mg/m2/day on days 1–4) and concurrent radiotherapy at 50.4 Gy. Long-term toxicity was evaluated according to the Common Terminology Criteria for Adverse Event Ver. 3.0. Results: The characteristics of both groups are as follows (J:R group): median age, 64:63; male/female, 178/29:42/5; PS 0/1/2, 90/104/1:33/14/0; stage IIA/IIB/III: 48/58/101:6/20/21. The median follow-up period was more than 60 months for both groups, with 5-year survival rates of 43.6% and 58.6% for the J and R group, respectively. The proportion of patients with grade 3/4 long-term toxicity in each group was as follows (J/R group): pleural effusion, (8.7%/0%; p = 0.036); pericardial effusion, (6.7%/2.1%; p = 0.196); radiation pneumonitis, (2.4%/4.2%); esophagitis, (0.9%/0%); and pericarditis, (2.4%/0%). Grade 3/4 late toxicity was observed more frequently in the J group (15.0%) than in the R group (6.4%) (p = 0.087). Treatment-related death due to pneumonitis was observed in only 1 patient in group J. Conclusions: The RTOG regimen at a dose of 50.4 Gy showed promising results while inducing lower late toxicity rates than when administered at 60 Gy.
Next-generation sequencing (NGS) of serum microRNA in hepatocellular carcinoma (HCC) patients treated with sorafenib and an mTOR inhibitor.
Authors: Kelley Robin Kate , Chang Aaron N. , Anguiano Esperanza , Hwang Jimmy , Stoppler Hubert J. , McWhirter Ryan M. , Parks Anna L. , Hameed Bilal , Fix Oren K. , Wayne Elizabeth M. , Nimeiri Halla Sayed , Munster Pamela N. , Venook Alan Paul , Goga Andrei
Published: February 2017

LBA204

Background: Noninvasive biomarkers are urgently needed in HCC. MicroRNA (miRNA) are small, noncoding RNA that regulate mRNA expression and are detectable in tumor tissue and extracellular compartments. miRNA signatures in blood specimens show association with HCC diagnosis but have not been explored as pharmacodynamic or predictive biomarkers. We present a pilot study to identify differentially expressed miRNA using NGS on serum from HCC patients at baseline and on targeted therapy, compared to controls. Methods: Serum samples were obtained from HCC patients enrolled on a clinical trial of sorafenib plus temsirolimus. Control sera were obtained from patients with non-malignant liver diseases (NMLD) and healthy volunteers (HV). Total RNA was extracted using RNAzol followed by library construction for each sample. Small RNA were separated by gel purification and sequenced by Illumina HiSeq 2500 at 5M+ reads per sample. Raw sequencing reads were mapped using Novoalign and quantified. Counts were normalized using an exogenous spike-in miRNA. Comparisons between HCC vs. control and baseline vs. on treatment cohorts were performed by linear regression (one-way ANOVA) and multiple-test corrected using Benjamini-Hochberg statistics. Candidate signature miRNA were derived using fold change, p-value, and abundance cutoffs. Results: Cohorts: HCC baseline (n=23) and paired on treatment (n=20), NMLD (n=12), and HV (n=10). HCC cohort: HBV+/dual 40%, HCV+ 32%. NMLD cohort: HCV+ 83%. Median RNA yield/200 µL was 410 ng (range: 69-1066) for HCC, 406 ng (range: 224-1100) for NMLD. The mapping rate ranged from 10-70%. Elevated AFP was associated with up-regulated miRNA identified in TCGA HCC cases, including miR-10a/b. No significant differences were observed for HBV+ vs. HCV+. Multiple oncomiRs appeared downregulated on treatment including Let-7 and miR-17/92 family members. Some miRNA isoforms were differentially regulated in each cohort. Conclusions: Serum miRNA in HCC patients demonstrate changes on treatment and can be characterized by NGS. Certain miRNA implicated in HCC appeared related to clinical covariates and warrant further study as novel biomarkers.
Multimodality treatment of colorectal peritoneal metastasis with perioperative systemic chemotherapy, cytoreductive surgery (CRS), and HIPEC: First safety results of the COMBATAC trial.
Authors: Piso Pompiliu , Koller Michael , Arnold Dirk , Schlitt Hans J. , Glockzin Gabriel
Published: February 2017

LBA382

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising therapeutic option as part of an interdisciplinary multimodal treatment regimen for selected patients with peritoneal metastasis arising from colorectal cancer. The COMBATAC trial evaluates the feasibility, safety, and efficacy of perioperative cetuximab-containing systemic polychemotherapy, CRS and bidirectional oxaliplatin-based HIPEC. Methods: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial recruiting patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal metastasis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Results: Preliminary data of the first 16 documented patients show a total number of 51 adverse events. According to CTCAE v4 the distribution of AE was 23 grade 1, 14 grade 2, 13 grade 3, and one grade 4, respectively. Of the 14 grade 3/4 adverse events three were chemotherapy-related, four surgery-related, and seven not directly treatment-related. Most common grade 3/4 complications were infection, thrombosis, and urinary tract obstruction. Conclusions: First data indicate that perioperative systemic polychemotherapy including cetuximab in combination with CRS and bidirectional HIPEC is feasible and might not lead to increased morbidity and toxicity rates. Nevertheless, the COMBATAC trial is still recruiting, and data regarding progression-free survival (PFS) and overall survival (OS) is not yet available. Clinical trial information: NCT01540344.
Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC).
Authors: Koopman Miriam , Simkens Lieke , May Anne , Mol Linda , van Tinteren Harm , Punt Cornelis J. A. ,   on behalf of the CAIRO3 Study Group
Published: February 2017

LBA388

Background: The optimal duration of chemotherapy and bevacizumab (bev) in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine (cap) + bev versus observation in mCRC patients (pts) not progressing during induction treatment with cap, oxaliplatin, and bev (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after six cycles of CAPOX-B were randomized between observation (arm A) or maintenance treatment with cap 625 mg/m2 bid daily continuously + bev 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were to be treated with CAPOX-B until 2nd progression (PFS2, primary endpoint). Secondary endpoints were overall survival (OS) and time to 2nd progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1, and quality of life. Preplanned subsetanalyses were performed. Results: A total of 558 pts were randomized. Median follow-up is 48 months. Upon PFS1, CAPOX-B was reintroduced in 61% of pts in arm A and 48% in arm B. Multivariable analyses for survival, with treatment adjusted for a series of pre-specified potentially confounding factors at baseline showed significant interactions for treatment (observation vs. maintenance) with resection of the primary tumor (yes vs. no) and synchronous or metachronous metastases at baseline (p values for interaction <0.0001). Especially pts with synchronous metastases with resected primary tumor (n=180) appear to benefit from maintenance treatment; median OS 18.0 months (observation arm) vs. 25.0 months (maintenance arm) (log-rank p value: <0.0001). Conclusions: Multivariable analysis showed significant interaction of treatment with some baseline covariates which were not equally distributed among both arms. The positive effect on survival for maintenance treatment with cap + bev is most obvious in pts with synchronous disease in whom the primary tumor was resected. Further details and final results on survival will be presented at the meeting. Clinical trial information: NCT00442637.
FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Brodowicz Thomas , Vrbanec Damir , Kaczirek Klaus , Ciuleanu Tudor-Eliade , Knittelfelder Regina , Lindner Elisabeth , Messinger Diethelm , Zielinski Christoph , Streubel Berthold
Published: February 2017

LBA391^

Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors [RAS wt] versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) [RAS mt]. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.
Final results of the Montpellier prostate cancer intensity modulated radiotherapy pilot study.
Authors: Charissoux Marie , Fenoglietto Pascal , Ailleres Norbert , Thézenas Simon , Rebillard Xavier , Llacer Moscardo Carmen , Thuret Rodolphe , Hay Meng Huor , Segui Bruno , Faix Antoine , Dubois Jean-Bernard , Azria David
Published: February 2017

105

Background: Thirteen hundred prostate cancer patients have been treated with Intensity modulated radiotherapy (IMRT) since 2001. We present the final results of the pilot study concerning the first 373 patients with a median follow-up of 72.7 months (range 0 to 130). Methods: All patients received the entire treatment course to a prescribed total dose of 80 Gy. No pelvic irradiation was applied. Androgen ablation therapy was delivered for 6 months and 2 to 3 years in intermediate and high-risk patients, respectively (n=142, 38%). Prostate-specific antigen (PSA) failure was defined as nadir + 2. Toxicity was assessed according to the National Cancer Institute (NCI)/Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Multivariate analysis using the Cox model was performed to assess factors that may impact on PSA relapse. Logistic regression was used to correlate clinical and physical parameters with grade 2 or higher gastro-intestinal and genitourinary toxicities. Results: Median age was 69 (range 40 to 81). One hundred thirty nine (37.3%), 167 (44.8%), and 67 (18%) patients were classified as low (group 1), intermediate (group 2), and high-risk (group 3) patients, respectively. The 5 year biochemical relapse-free survival (5y-biochemical recurrence-free survival [bRFS]) was 85.7% (95% CI, 0.81-0.89). For the three prognostic groups, 5y-bRFS was 91% (95% CI, 0.85-0.95), 82% (95% CI, 0.75-0.87), and 80% (95% CI, 0.67-0.88) for groups 1, 2, and 3, respectively. Multivariate analysis showed that the absence of hormonotherapy in the group 2 and the number of positive biopsies impact on PSA relapse (p=0.04, HR 1.8 and p=0.01, HR 2.13, respectively). The incidence of late grade 2 or higher rectal and urinary toxicities were 10.5% and 12.7%, respectively. The dose received by 50% (D50) of the rectum was the only factor significantly correlated with late grade 2 or higher rectal toxicities (p = 0.04). Similarly, the dose received by 50% (D50) of the bladder was the only factor significantly correlated with late grade 2 or higher bladder side-effects (p = 0.02). Conclusions: IMRT to 80 Gy can provide good to excellent carcinologic results and low late toxicity rates in all prostate cancer subgroups. Hormonotherapy combined to high dose IMRT seems to be a serious option to consider in intermediate-risk patients. Clinical trial information: ICM 2001-13.
Molecular profiling of advanced refractory prostate cancer.
Authors: Feldman Rebecca A. , Basu Gargi Dan , Xiu Joanne , Arguello David , Millis Sherri Z. , Bender Ryan , Gatalica Zoran , Paul Les , Myers Charles E.
Published: February 2017

107

Background: Prostate cancer is the second leading cause of cancer-related death among men in the U.S. Forty percent of men diagnosed will develop metastatic disease, which has few treatment options. We aim to describe the molecular profile of prostate cancer tumors and potential for novel therapeutic options. Methods: We reviewed profiling data of over 330 patients from a large referral laboratory (Caris Life Sciences, Phoenix, AZ) for biomarkers of drug response. Multiple methodologies were employed: sequencing (NGS, Sanger, pyrosequencing), in-situ hybridization (fluorescent and chromogenic), and immunohistochemistry. Results: High expression was observed for AR, MRP1, TOPO1, TLE3 and EGFR, with positivity rates of 89%, 87%, 63%, 48%, and 47%, respectively. Low expression was observed for TS, PGP, TUBB3, RRM1, PTEN and MGMT, with negativity rates of 94%, 87%, 75%, 69%, 54%, and 45%, respectively. Gene copy number increases for EGFR and cMYC were observed in 13% of patients. Sequencing data showed a 48% mutation rate for TP53, 18% for PTEN, 9% for CTNNB1, 8% for PIK3CA, 5% for RB1, ATM, and cMET, and approximately 2% for K/HRAS, ERBB4, ALK, BRAF, and cKIT. Targeted therapy options include imatinib for patients with high cKIT or PDGFRA (9 to 10%) and cetuximab for patients with EGFR positivity (13 to 47%). Promising agents may be considered, including cabozantinib, based on 4% of cohort with cMET aberrations or PAM pathway inhibitors (BEZ234, everolimus) based on approximately 30% of cohort with PIK3CA pathway activation. Lastly, HDAC inhibitors have recently been linked to cMYC driven cancers (13% amplified). 5-FU, gemcitabine, and temozolomide chemotherapies may be options, as approximately 70% of cohort with low TS, RRM1, or MGMT. Biomarker guidance for common prostate cancer drugs such as cabazitaxel is also provided, based on approximately 70% of cohort with low TUBB3 or PGP, or high TLE3. Also, continued dependence on androgen signaling is exhibited by 89% of cohort with high AR, indicating potential utility of anti-androgen agents like enzalutamide. Conclusions: Tumor profiling identified small subsets of patients that may benefit from targeted agents approved for other solid tumors (imatinib, cetuximab), promising therapies in clinical trials (cabozantinib) or agents not routinely used for prostate cancer (gemcitabine).
Patient-reported outcomes using a validated LENT-SOMA questionnaire for post-prostatectomy radiotherapy.
Authors: Choudhury Ananya , Agarwal Arjun , Swindell Ric , Tran Anna , Alam Nooreen Sarah , Coyle Catherine , Livsey Jacqueline E. , Wylie James , Logue John P. , Elliot Tony
Published: February 2017

118

Background: Although local post-operative radiotherapy (RT) improves biochemical progression free survival, there is no evidence of overall survival benefit. With a trend for radical prostatectomy (RP) and radiotherapy for more advanced disease, the debate continues about the merits of multimodality treatment in these patients and the importance of survivorship. We assessed prospectively the effect of combination surgery and radiotherapy on the long term outcomes of patients. Methods: A validated LENT-SOMA (LS) questionnaire was posted to 238 UK patients treated from 2004 to 2009 with post-RP RT to assess patient-reported outcomes after prostate cancer treatment. Patients were treated with hypofractionated 3D conformal RT using image guidance delivering 52.5Gy in 20 fractions over 28 days to the prostate bed, but not to whole pelvis. LS responses were compared with patient perception of their bowel, bladder and sexual function post-RP. Results: Median follow up from RT was 6.26 years. Fifty five percent (130 out of 238) of patients returned questionnaires. Median maximum LS scores for bladder and bowel were three with over 75% of patients reporting at least one occasion of bowel or bladder difficulty in the past month. There was no difference in mean LS scores when compared pre and post RT. No patients had grade 3/4 RTOG toxicities. The median maximum LS score for sexual function was four. There was a significant difference in mean LS scores for sexual function (p=0.001) when compared pre and post radiotherapy. LS scores were not affected by post-RT hormones (26 out of 130 patients) or the time between RP and RT (median 1.76 years). Conclusions: The validated LS questionnaires revealed changes in sexual function post-RT compared with pre-RT were greater than bowel or bladder function. It remains difficult to determine the relative contributions of RP and RT to the late toxicity of multimodality treatment. Ongoing large multi-centre randomised control trials such as the UK-led RADICALS trial will answer questions about timing of RT and need for additional hormones. With the increasing importance of survivorship, it should be noted that prostate-specific antigen control at the expense of toxicity without an overall survival advantage should be treated with caution.
Long-term treatment with testosterone undecanoate injections and its effect of prostate cancer incidence in hypogonadal men.
Authors: Haider Ahmad , Zitzmann Michael , Yassin Aksam
Published: February 2017

119

Background: Concerns regarding the safety of testosterone treatment, particularly regarding prostate cancer in elderly men, still hamper the use of testosterone in hypogonadal men. Methods: Registry studies of 942 men with testosterone levels less than or equal to 12.1 nmol/L from three German centers. Patients received testosterone undecanoate for up to 16 years. Results: In cohort A (mean age: 57.70 ± 6.76 years; Bremerhaven), prostate-specific antigen (PSA) increased from 1.77±0.97 to 2.0±1.01 ng/ml (p=0.0021). Prostate volume increased from 28.34±10.79 to 30.72±14.28 ml (p<0.0001). Five out of 300 patients were diagnosed with prostate cancer. The proportion was 1.7% with an incidence of 39.4 per 10,000 patient-years. In cohort B (mean age: 59.53 ± 8.35 years; Norderstedt), PSA increased from 0.86±0.57 to 1.38±0.49 ng/ml (p<0.0001). Prostate volume increased from 27.9±8.15 to 36.98±7.22 ml (p<0.0001). Six out of 261 patients were diagnosed with prostate cancer. The proportion was 2.3% with an incidence of 54.5 per 10,000 patient-years. One patient in cohort B was treated with external beam radiation, all other patients underwent radical prostatectomy. In cohort C (mean age: 42.6 ± 13.4 years; Muenster), PSA increased from 1.6±0.4 to 1.9±0.4 (p<0.001). Prostate volume increased from 16.9±5.1 to 19.9±5.3 ml (p<0.001). No patient was diagnosed with prostate cancer. Conclusions: The PLCO trial reported an incidence of 116 per 10,000 patient-years (Andriole, NEJM 360(13):1310-9), the ERSPC trial 96.6 (Schröder, NEJM 366(11):981-90). Although these screening trials cannot be directly compared to our registries of hypogonadal men receiving testosterone replacement therapy, the incidence of prostate cancer in our registry studies does not suggest an increased risk in hypogonadal men on long-term testosterone treatment.