bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of AZD4547 in FGFR amplified tumours: Gastroesophageal cancer (GC) cohort pharmacodynamic and biomarker results.
Authors: Smyth Elizabeth Catherine , Turner Nicholas C. , Pearson Alex , Peckitt Clare , Chau Ian , Watkins David J. , Starling Naureen , Rao Sheela , Gillbanks Angela , Kilgour Elaine , Sumpter Katherine Anne , Smith Neil R. , Cutts Ros , Rooney Claire , Thomas Anne L. , Ajaz Mazhar A. , Chua Sue , Brown Gina , Popat Sanjay , Cunningham David 
Published: February 2017

154 Background: FGFR amplified tumors demonstrate oncogene addiction in vitro and in vivo. We examined the efficacy of AZD4547, an orally available inhibitor of FGFR 1, 2 & 3, in FGFR1/2 amplified cancers, and herein present results from a gastroesophageal cancer (GC) cohort. Methods: Phase II Simon 2 stage design (3 independent cohorts) for previously treated patients (pts) with advanced FGFR1 (HER2 negative breast/NSCLC) or FGFR2 amplified tumors. FGFR1/2 amplification was centrally assessed using FISH. Pts received AZD4547 80mg twice daily. Primary endpoint is centrally confirmed response rate (RR), with the study concluding efficacy if ≥ 3/17 patients in a cohort had a confirmed response. PET-CT was performed at baseline, D14 and 8 wks, biopsy at baseline and D14 and optionally on progression. Biomarkers included FGFR copy number variation in tumor and plasma, NanoString gene expression, MIRAX digital FISH imaging and phospho-immunohistochemistry. Results: Of 288 pts with screening results, 9% (12/138) gastroesophageal (GC) pts had FGFR2 amplification with 5% (7/138) highly amplified (FGFR2 ratio > 5.0). Confirmed RR was 33% (3/9) in FGFR2 amplified GC. Mean duration of response in responders was 5.7 months. All GC responders had a PET response on D14 PET. Common toxicities (all pts n = 18) included fatigue (72%), constipation (50%) mucositis, skin and eye changes (44% each). Phospho-immunohistochemistry on pre-treatment and D14 biopsies demonstrated an increase in S6 and decrease in p-ERK following treatment. Using digital droplet PCR (ddPCR) elevated FGFR2 copy number was detected in free plasma DNA of all responding GC pts, and no non-responding pt. NanoString and MIRAX imaging analysis revealed the presence of truncated C3 FGFR2 isoform and high level homogenous FGFR2 amplification in all GC responders respectively. Conclusions: AZD4547 demonstrated promising activity in FGFR2 amplified GC. On treatment biopsies demonstrate evidence of target inhibition. Clonal, high level amplification appears to be required for response to AZD4547. As all responding patients had FGFR2 copy number gain detected in plasma using ddPCR this technique will be developed as a screening tool. Clinical trial information: NCT01795768.
Pattern of regional recurrence after curative resection in locally advanced adenocarcinoma of gastroesophageal junction: Implication for elective lymphatic target delineation of radiotherapy.
Authors: Zhang Jiajia , Jin Jing , Xin Wang 
Published: February 2017

158 Background: To investigated the regional recurrence pattern of Siewert type II/III AGE patients after curative resection and refine the clinical target volume (CTV) delineation of radiotherapy. Methods: From 2009 to 2013, 78 patients who were histopathologically diagnosed with locally advanced AGE (T3/4 or any N+, Siewert II/III) after curative resection and confirmed of regional recurrence in follow-up CT images were retrospectively reviewed. First regional recurrence was recorded and one diagnostic radiologist with specialty of gastrointestinal tract investigated. Pattern of regional failure at each node station were analyzed. Reference CT images were obtained from a healthy volunteer. We then delineated the epicenters of recurrence sites at the equivalent location, based on the same vessels of reference CT images compared with the recurrence CT images on Pinnacle planning system. The combined contour of all recurrence sites was presented on a digitally reconstructed radiograph (DRR) image. Results: Most recurrence occurred within 2 years of follow-up (Median, 10.9 m). Of all, 35 (44.9%) patients had regional failure (RF) only; 24 (38%) had RF simultaneous with distant failure; 11 (14.1%) were locoregional, and 8 (10.3%) had concurrent distant and locoreginal failure. The most common recurrent node stations were No.16 (62.8%), No. 9 (32.1%), No. 11 (24.4%), No. 8 (17.9%), No. 7 (16.7%), No. 112 (12.8%), No. 4 (12.8%) and No. 12 (10.3%), respectively. 11 patients (14.1%) had recurrence at mediastinal lymph nodes. There was no significant difference of NF between Siewert type II and III AEG except for No. 9 (42.2% vs 18.2%, P = 0.027). The frequency and location of RF was shown by CT and digitally reconstructed radiograph (DRR) images. A three-dimensional (3D) atlas based on vessel delineation and distribution of RF was established. Conclusions: The most prevalent regional recurrence in Siewert type II/III AEG patients after curative resection was along the abdominal aorta, celiac artery and splenic artery. Our findings suggest a modified elective lymphatic target volume for IMRT contours in those patients.
Outcomes in patients with brain metastasis from esophageal carcinoma.
Authors: Saeed Nadia , Kothari Nishi , Mellon Eric Albert , Hoffe Sarah E. , Frakes Jessica M. , Shridhar Ravi , Pimiento Jose Mario , Meredith Ken Lee , Tran Nam D. , Almhanna Khaldoun 
Published: February 2017

159 Background: Brain metastases from esophageal carcinoma have historically been rare. With improvements in systemic therapy, patients are living longer and the incidence of brain metastasis (mets) is expected to rise. However, there is no consensus on management. We present our single institution experience with brain mets from esophageal cancer. Methods: We retrospectively identified 49 patients (pts) with brain mets from primary esophageal cancer who were treated at our tertiary referral center between 1998 and 2015. Medical records were reviewed to collect demographic and clinical information. Results: Median age at diagnosis of the primary esophageal cancer was 60 years. 41 pts were male. 39 pts had adenocarcinoma, 4 had squamous cell carcinoma, 4 had poorly differentiated carcinoma, and 1 had neuroendocrine carcinoma. Stage at diagnosis ranged from I-IV. 7pts had synchronous brain mets, defined as occurring within 3 months of diagnosis. The remaining pts were found to have brain mets more than 3 months after diagnosis. 27 pts had a solitary met, 12 had two lesions, and the rest had multiple lesions. For primary treatment, 12 pts had surgery only, 8 had stereotactic radiosurgery (SRS) as a definitive treatment, and the remainder had a combination of surgery, SRS, and whole brain radiation therapy. Median survival following esophageal cancer diagnosis was 24 months (range 3-71), and median survival after the identification of brain mets was 5 months (range 1-52). Using the recursive partitioning score (RPA), 15 pts had class I disease and 28 had class II, and 6 had class III disease. Those with class I or II disease had significantly improved overall survival (p < 0.001). Conclusions: Brain metastases from esophageal cancer are rare with overall poor prognosis. However, some pts can have prolonged survival. In the largest series to date, we found that pts with controlled systemic disease and limited number of brain lesions who had definitive therapy (surgery or SRS) had better outcome. Aggressive treatment may improve outcomes.
Pembrolizumab (MK-3475) plus 5-fluorouracil (5-FU) and cisplatin for first-line treatment of advanced gastric cancer: Preliminary safety data from KEYNOTE-059.
Authors: Fuchs Charles S. , Ohtsu Atsushi , Tabernero Josep , Van Cutsem Eric , Wang Jiang Dian , Lam Baohoang , Koshiji Minori , Bang Yung-Jue 
Published: February 2017

161 Background: Standard first-line treatment for advanced gastric cancer includes combination chemotherapy with a platinum agent and a fluoropyrimidine. The anti–PD-1 humanized monoclonal antibody pembrolizumab (pembro) has shown promising antitumor activity as monotherapy in patients (pts) with advanced gastric cancer. We report preliminary safety data for pts with advanced gastric cancer treated with pembro + cisplatin and 5-FU in the multicohort, phase 2 KEYNOTE-059 study (NCT02335411). Methods: Eligible pts were aged ≥ 18 y and had HER2– relapsed or metastatic gastric or gastroesophageal junction adenocarcinoma, ECOG PS 0-1, and no prior therapy for metastatic disease. Pts received pembro 200 mg + 5-FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan) + cisplatin 80 mg/m2 Q3W for 6 cycles followed by pembro + 5-FU for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Primary end point was safety and tolerability of the combination. Results: Of the 17 pts enrolled (10 from Asia, 7 from outside Asia), 70.6% were men, and median age was 58.0 y. Three pts (17.6%) had a prior gastrectomy—2 total, 1 partial. As of the Aug 12, 2015, data cutoff date, median follow-up duration was 3.6 mo (range 2.6-5.4), and pts received a median of 5 treatment cycles (range 3-7). Only 1 pt (5.9%) discontinued treatment (due to progressive disease). There were no treatment-related deaths or discontinuations. Twelve pts (70.6%) experienced treatment-related adverse events (AEs) of any grade, most commonly neutropenia/decreased neutrophils (n = 7, 41.2%), stomatitis (n = 6, 35.3%), and decreased appetite (n = 5, 29.4%). Eight pts (47.1%) experienced ≥ 1 grade 3-4 treatment-related AE; only neutropenia/decreased neutrophils (n = 4 [23.5%] grade 3, n = 3 [17.6%] grade 4) occurred in > 1 pt. AEs of interest based on immune etiology, regardless of attribution by investigator, were grade 2 infusion-related reaction and grade 2 pruritus (n = 1 [5.9%] each). Conclusions: Preliminary data from KEYNOTE-059 suggest the combination of pembro, cisplatin, and 5-FU has a manageable safety profile as first-line therapy in pts with advanced gastric cancer. Clinical trial information: NCT02335411.
Risk factors for survival in early T stage gastric cancer.
Authors: Ikoma Naruhiko , Elimova Elena , Blum Mariela A. , Ajani Jaffer A. , Chiang Y. Sabrina , Fournier Keith F. , Mansfield Paul F. , Badgwell Brian D. 
Published: February 2017

162 Background: Early T stage gastric cancer in the West is rare, with limited data to guide treatment decisions. The purpose of this study was to identify clinicopathologic factors associated with survival in early T stage gastric adenocarcinoma. Methods: The medical records of 8,260 patients with gastric or gastroesophageal adenocarcinoma presenting to MD Anderson Cancer Center (1/1995 to 12/2013) were reviewed to identify those who underwent gastrectomy with a pathological diagnosis of T1 or T2 adenocarcinoma. Associations between clinicopathologic factors and overall survival were examined with Cox Regression model. Results: We identified 121 patients with T1 or T2 tumors (49 [40.5%] T1a, 49 [40.5%] T1b, and 23 [19.0%] T2) who underwent R0 resection without neoadjuvant treatment. Mean age was 62 years, and 53% were male. Races included 53% Caucasian, 9% African-American, 17% Hispanic, and 22% Asian. Tumor locations included 10% in the esophagogastric junction and 49% confined in the antrum. Of the 121 study patients, 55% underwent extended lymph node dissection (D1+/D2) and 60% had more than 15 lymph nodes examined pathologically. Pathological analysis showed 77% of patients with poorly differentiated tumors and 27% were positive for lymph node metastasis. Postoperatively, 12% underwent adjuvant chemotherapy. The median follow-up was 5.7 years, and overall 5-year survival was 89% (98%, 93%, and 66% in T1a, T1b, and T2, respectively). Univariate analysis revealed higher risk of death in patients with T2 tumors and African-American race. N stage did not reach statistical significance for survival (HR 3.6, 95% confidence interval 1.51-8.79; p = 0.07). On multivariate analysis, T2 stage was the only variable associated with survival (HR 2.8, 95% confidence interval 1.11-7.12; p = 0.03). Conclusions: In patients with T1 or T2 stage gastric cancer, T stage was associated with diminished survival, whereas nodal status was not. Additional studies focused on patients with early-stage gastric cancer in Western populations are needed to determine which patients would benefit from preoperative or adjuvant therapy.
Prospective evaluation of quality of life (QOL) during a phase I/II study of adjuvant chemotherapy with image-guided high-precision radiotherapy for completely resected gastric cancer.
Authors: Goody Rebecca Barbara , Mackay Helen , Pitcher Bethany , Oza Amit M. , Brierley James D. , Kim Joon-Hyung J. , Wong Rebecca , Kassam Zahra , Swallow Carol Jane , Cummings Bernard , Dinniwell Robert Edward , Knox Jennifer J. , Brade Anthony M. , Dawson Laura A. , Pintilie Melania , Ringash Jolie 
Published: February 2017

164 Background: Adjuvant chemoradiotherapy improves overall and relapse free survival in patients with completely resected gastric cancer, but confers toxicity. This prospective phase I/II clinical trial assessed the toxicity, efficacy and QOL when adding bi-weekly cisplatin to adjuvant chemoradiotherapy with infusional 5-fluorouracil (5-FU). Phase I data showed promising outcomes with acceptable toxicity. Methods: Treatment comprised 45 Gy in 25 fractions of image-guided 3D-CRT or IMRT concurrently with weeks 3-7 of 12 weeks of infusional 5-FU. Cisplatin (up to bi-weekly) was added in a standard dose-escalation protocol. Patients completed the EORTC QLQ-C30 at baseline, end of radiotherapy, 4 weeks post chemotherapy and at 1 and 2 years. Results: Among 55 participants (mean age 54, range 28 to 77; 55% male; median follow-up 3.03 years), QOL compliance ranged from 93% at baseline to 70% at 4 weeks post-treatment. Maximal tolerable dose of cisplatin was 40 mg/m2 bi-weekly for 4 cycles. OS and DFS rates are 85% and 74% respectively at 2 years. Mean scores for global QOL (median difference = -25, p < 0.0001), role and social functioning, fatigue, nausea and vomiting, and appetite declined at completion of radiation; physical functioning showed a statistically significant decline of borderline clinical importance (median difference = -6.7, p <.0001). All scales recovered by 4 weeks after chemotherapy except fatigue, which returned to baseline by one year. Conclusions: Adjuvant gastric chemoradiotherapy incorporating cisplatin worsened global QOL, fatigue, nausea and vomiting and appetite. Most scales recovered by 4 weeks post-chemotherapy. This regimen is tolerable not only by observer rated toxicity, but also by patient reported QOL measures. Clinical trial information: NCT00188266.
Patterns and predictors of locoregional recurrence following neoadjuvant chemoradiation for esophageal cancer.
Authors: Blackham Aaron Udell , Jin Will , Almhanna Khaldoun , Fontaine Jacques-Pierre , Hoffe Sarah E. , Frakes Jessica M. , Venkat Puja , Pimiento Jose Mario 
Published: February 2017

173 Background: Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrences (LRR) are common. Specific risk factors for LRR have yet to be identified. Methods: Patients with esophageal cancer who were treated with nCRT and esophagectomy were identified from a single institution, prospectively maintained database(1996-2013). Timing and locations of recurrences were described and predicting factors of LRR were analyzed. Results: Out of 456 patients treated with nCRT for esophageal cancer, 167 patients developed known recurrence. Locoregional and distant recurrences were observed in 69(15.1%) and 140(30.9%) patients, respectively. Median recurrence-free survival was 38.5 months with a median follow-up of 30.4 months. Sixty-eight patients(40.7%) developed recurrence at multiple sites. The median time to recurrence was 13.5 months and survival following recurrence was only 8.0 months in the 27 patients(16.2%) with solitary LRR. Overall survival in patients with solitary LLR was 23.6 months, compared to 20.8 months in all patients who developed distant recurrence. Univariate analysis identified lymph node ratio > 0.5(OR 2.42, p = 0.030), non-complete pathologic response(OR 1.90, p = 0.022), positive margins(OR 3.58, p = 0.028) and lymphovascular invasion(OR 2.82, p = 0.001) as significant predicting factors for LRR. While perineural invasion(p = 0.055), nodal stage(0.053) and use of adjuvant therapy(p = 0.060) approached significance, other factors such as tumor stage, type of surgery (Ivor-Lewis vs transhiatal), radiation dose and use of IMRT were not significant predictors of LRR. Only lymphovascular invasion was an independent predictor of LRR. Conclusions: Prognosis following LRR in patients with esophageal cancer treated with nCRT is poor but is better than in patients who develop distant recurrence. High lymph node ratio, positive margin status, non-complete pathologic response and the presence of lymphovascular invasion are predictive of LRR following nCRT for esophageal cancer.
Trimodality treatment for locally advanced esophageal malignancies.
Authors: Thomas Tarita , Mathew Maya , Elahi Nimra , Murata Stephen 
Published: February 2017

174 Background: This study sought to review a single-institution experience with the management of patients with locally advanced esophageal adenocarcinoma, focusing on outcome and patterns of failure and factors affecting failure. Methods: A retrospective review of patients with locally advanced esophageal malignancies who were treated at our institution from 2002 to 2014. All patients underwent concurrent chemoradiation and surgery. Radiotherapy was delivered using 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT). Locoregional failure-free survival (LRFFS), distal metastasis free survival (DMFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Different factors which can affect the failure pattern were compared. Results: A total of 46 patients were analyzed. Median age was 66 years (range, 44 to 80 years). Forty three patients (93%) were men. All patients had adenocarcinoma (46% with moderately differentiated & 54% with poorly differentiated histology) involving the distal third of the esophagus. Ninety three percent were treated with 3DCRT while 7% received IMRT with a median dose of 50.4 Gy. 72 % of the tumors were downgraded after the neoadjuvant therapy, with 43 % complete response. With a median follow-up time of 22 months (range, 1 to 116 months), locoregional failure was observed in 10 patients (21%) and distant metastasis in 18 patients (39%). Among the 32 patients who died 16 patients died of disease progression and 6 patients died of post-operative complications. BMI (Body mass index) at the time of diagnosis, time elapsed between chemoradiation and surgery, history of weight loss at presentation and insertion of the J tube before neoadjuvant therapy did not affect the outcomes as per our study. Conclusions: Thoughneoadjuvant chemoradiation followed by surgery produces good pathological response to locally advanced esophageal malignancies, those results are not extrapolated to survival rates with most of the patients dying of distant metastasis. Further multi-institutional studies are required to assess other factors which are affecting the survival of esophageal cancer patients.
Tumor and plasma biomarker analysis from the randomized controlled phase II trial (RCT) of tivantinib in second-line hepatocellular carcinoma (HCC).
Authors: Rimassa Lorenza , Abbadessa Giovanni , Personeni Nicola , Porta Camillo , Borbath Ivan , Daniele Bruno , Van Laethem Jean-Luc , Van Vlieberghe Hans , Trojan Jorg , de Toni Enrico , Peck-Radosavljevic Markus , Finn Richard S. , Raoul Jean-Luc , He Aiwu Ruth , Lamar Maria , Wang Yunxia , Von Roemeling Reinhard W. , Schwartz Brian E. , Bruix Jordi , Santoro Armando 
Published: February 2017

197 Background: Tivantinib, an oral MET inhibitor, showed activity in patients (pts) MET-High at immunohistochemistry (IHC) in randomized, placebo controlled studies in HCC, NSCLC, CRC, and prostate cancer. ARQ 197-215 was a RCT of tivantinib in second-line HCC. The study randomized 107 pts 2:1 to tivantinib capsules or placebo, reached the primary endpoint of time to progression in the intent-to-treat population and the pre-specified secondary efficacy endpoints, including OS, in MET-High pts. Tumor MET was also found to be a strong independent prognostic factor. This analysis aims to study prognostic and predictive value of tumor and circulating biomarkers. Methods: Circulating MET, HGF, and AFP were centrally analyzed by ELISA and median values were used as cut-offs to determine High or Low status except for AFP, where the 75th percentile was also used. Tumor MET was centrally analyzed and considered High if staining was >2+ in >50% of cells at IHC. Results: Circulating MET was prognostic (N=102; OS: 4.6 vs 8.9 months in High vs Low, HR=0.61, p=0.023) and trended towards predicting tivantinib’s activity. MET was also a pharmacodynamic marker: pts on tivantinib with a MET reduction over time survived longer; MET was reduced in pts stable on tivantinib but not on placebo. Circulating HGF was prognostic (N=102; OS: 5.0 vs 9.0 months in High vs Low, HR=0.6, p=0.02) and changes over time correlated with outcome. AFP by the 75th percentile was prognostic (N=104; OS: 3.0 vs 7.9 months in High vs Low, HR=0.36, p<0.0001). Median IHC score (H-Score) was 175 for tumor MET-High, 40 for MET-Low pts (N=77). MET was highly expressed in 40% of biopsies taken before and in 82% of biopsies taken after sorafenib. A significant interaction between tivantinib and tumor MET in terms of OS was observed (p=0.039). No biomarker except for tumor MET was predictive of response to tivantinib. Conclusions: A clear prognostic value was found for circulating MET, HGF, and AFP by the 75th percentile. Tumor MET was highly prognostic and predictive. IHC results on over 900 tumor samples analyzed in the ongoing METIV-HCC phase 3 study will also be presented. Clinical trial information: NCT00988741.