bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of vater.
Authors: Gulhati Pat , Raghav Kanwal Pratap Singh , Shroff Rachna T. , Varadhachary Gauri R. , Kopetz Scott , Javle Milind M. , Qiao Wei , Wang Huamin , Morris Jeffrey , Wolff Robert A. , Overman Michael J.
Published: February 2017

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Background: Capecitabine with oxaliplatin (CAPOX) is used in front-line management of metastatic small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). In a prior single arm phase 2 study (n = 30), CAPOX showed an overall response rate (ORR) of 52%. The purpose of this study was to evaluate safety and activity of bevacizumab and CAPOX in this population. Methods: We conducted a single-center open-label single arm phase 2 study in patients with treatment naïve metastatic SBA and AAC between 8/2011 to 11/2014. Prior fluoropyrimidine-based adjuvant therapy was allowed if completed ≥ 52 weeks. Bevacizumab-CAPOX was administered as a 21-day cycle with capecitabine 750 mg/m2 orally twice daily on days 1-14, oxaliplatin 130mg/m2intravenously on day 1 and bevacizumab 7.5mg/kg intravenously on day 1. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary objectives included ORR, overall PFS, overall survival (OS) and toxicity. Results: A total of 30 patients with median age of 63 years (range 33-78) were enrolled. Six (20%) patients had AAC and 24 (80%) had SBA (duodenal: 18). Treatment was well tolerated and most common grade 3/4 toxicities included fatigue (23%), hypertension (23%), neutropenia (30%), and diarrhea (10%). Common grade 2 toxicities included anorexia (50%), fatigue (47%), and nausea (37%). 4 patients remain on study treatment to date. In 29 evaluable patients the ORR was 48.3% (1 complete and 13 partial responses). Eleven (37.9%) patients had stable disease. The PFS at 6 months was 68% (95% CI: 52%-88%). The median PFS and median OS were 8.7 (95% CI: 6.6-13.4) and 14.98 (95% CI: 10.2-21.3) months, respectively. Comparing the current study to a subset of 25 patients with metastatic disease from our prior phase 2 CAPOX study demonstrated similar ORR, 48.3% vs. 52% (p = 0.79) and PFS 8.7m vs. 6.6m (p = 0.73). Conclusions: In patients with untreated metastatic SBA and AAC, therapy with bevacizumab and CAPOX was well-tolerated and showed efficacy comparable to published regimens. Further studies are warranted to evaluate the benefit of targeting angiogenesis in this rare tumor.
A proposal for the management guideline of superficial esophageal squamous cell carcinoma: After endoscopic resection.
Authors: Lee Yong Chan , Park Jun Chul , Shin Sung Kwan , Lee Sang Kil , Lee Hyun Jik
Published: February 2017

145

Background: We tried to analyze and deduce a treatment guideline after endoscopic resection of superficial esophageal squamous cell carcinoma in a retrospective analysis. Methods: Medical records of 37 patients who had been treated by endoscopic resection during a 6-year period in single institution were retrospectively analyzed. Results: Mean tumor size was 11.5±5.5 mm (range 3-31). Thirty-one lesions (83.8%) were treated by endoscopic submucosal dissection and 6 lesions by endoscopic mucosal resection (16.2%). En bloc resection rate and complete resection rate was 91.9% and 81.8%, respectively. The tumor invasion depth was diagnosed as epithelium: 5(13.5%), lamina propria mucosa: 12 (32.4%), muscularis mucosa: 10 (27.0%), submucosa: 10 (27.0%) respectively. The lymphovascular invasion was 3 lesions (8.1%). The rates of adverse events were 13.5% including 3 cases (8.1%) of perforation. Ten patients of the invasion depth as muscularis mucosa and submucosa received additional treatments including 6 patients of esophagectomy, 3 patients with radiotherapy and 1 patient with chemoradiotherapy. One patient of lamina propria received radiotherapy due to resection margin positive. The median follow-up duration was 22 month (range, 4-79) and there was no recurrence or metastasis during follow-up. Conclusions: We propose that adequate tailored management strategy after endoscopic resection of superficial esophageal squamous cell carcinoma may provide the favorable clinical results in outcome in treating early stage esophageal carcinoma.
The prognostic significance of perineural invasion in patients with esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy.
Authors: Patel Ankur Kaushik , Pan Xueliang Jeff , Williams Terence M , Wuthrick Evan John
Published: February 2017

146

Background: Perineural invasion (PNI) is the process of neoplastic invasion of nerves. PNI has been reported as a prognostic indicator in malignancies of the pancreas, stomach, colon, rectum, prostate, head and neck, and biliary tract. However, studies examining the prognostic significance of PNI in esophageal cancer have shown inconsistent results. Analyses in patients with esophageal adenocarcinoma (EAC) have alternatively shown PNI to be a significant and a nonsignificant predictor of OS and DFS in both univariate and multivariate analysis. The majority of these studies analyzed patients who had not received any preoperative therapy. We sought to identify the prognostic significance of PNI in patients with EAC treated with neoadjuvant chemoradiotherapy (nCRT). Methods: We performed a retrospective analysis of 108 patients treated with nCRT and surgery for EAC at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute from 1996-2015. The final analysis identified 73 patients with data on PNI. We evaluated the association of PNI with disease-free survival (DFS), loco-regional progression-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) using log-rank and Cox proportional hazard modeling. Results: Of 73 patients, 17 patients (23%) had PNI and 56 patients (77%) did not have PNI at the time of surgery. The median follow-up was 15.3 months (range 5.8 to 179.3 months). The median DFS was 12.4 months for PNI+ and 36.4 months for PNI- (p = 0.042). The median LRFS was 48.2 months for PNI+ and median not reached for PNI- (p = 0.003). We did not detect a significant association between the presence of PNI and worse OS or DMFS. In a multivariate model including age, sex, gastric involvement, biopsy grade, presence of pathologic complete response, and pathologic N stage, PNI remained a significant independent predictor of LRFS (HR 0.37, 95% CI 0.14 to 1, p = 0.05). Conclusions: In patients with esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy, PNI discovered at the time of surgery is significantly associated with worse DFS and LRFS.
Prospective results of perioperative chemotherapy (PCT) with cisplatin and irinotecan for locally advanced gastric cancer.
Authors: Pereira Guilherme Luiz Stelko , Fonseca Leonardo Gomes da , Ramos Marcus Fernando Kodama Pertille , Ribeiro Ulysses , Pereira Gabriel , Pereira Marina Alessandra , de Mello Evandro Sobroza , Sabbaga Jorge , Hoff Paulo Marcelo
Published: February 2017

147

Background: An overall survival (OS) benefit with PCT over surgery alone for locally advanced gastric cancer was seen in phase III trials. The best PCT regimen is uncertain and options based in infusional 5-FU or capecitabine have cost limitation in the context of Brazilian public health system. The combination of cisplatin and irinotecan is active in the metastatic setting, with no need of ambulatory infusion devices. The aim of this study is to evaluate safety and preliminary efficacy of this scheme as PCT. Methods: This prospective single arm study included patients (pt) with locally advanced gastric cancer, T3/T4 and/or evident lymph node involvement, to receive PCT cisplatin (30 mg/m2) and irinotecan (60 mg/m2) D1 and D8, each 21 days, in total of 6 cycles (Cy). Results: Between June/2011 and January/2014, 25 pt were included, with the following characteristics: 64 years (34-78) as median age; 10 (40%) pt with intestinal subtype and 10 with diffuse; 24% of cases were proximal gastric tumors; 20% had dysphagia and 24% bleeding signs before treatment. The median number of Cy before surgery was 3; 19 (76%) pt had surgery and 8 (32%) re-started Cy after surgery. Toxicity grade 3 or 4 was seen in 13 (52%) pt and 3 had unexpected arterial ischemic events. Radiologic progression occurred in 8 (32%) pt. Of the 21 tissue samples available, the expression of MLH-1, HER-2 (+++), p53, p16, Ki67 and EGFR was detected in 100% (21/21), 9.5% (2/21), 90.5% (19/21), 81% (17/21), 100% (11/21 < 50% and 10/21 > 50%) and 100% (10/21 +1/2 and 11/21 +3/4) of the cases, respectively. No correlation was seen between them and pathologic response. With a median follow up of 382 days, 13 (52%) pt were alive and the median OS was 15.2 (IC95% 4.9-24.5) months. In a univariate analysis, dysphagia, less than 3 Cy, progressive disease and neutrophil-to-Lymphocyte ratio (NLR) > 2, were significantly related to shorter OS. In multivariate analysis, only NLR > 2 (p = 0.019) and dysphagia were negatively impacting on OS (p = 0.02). Conclusions: Although PCT with cisplatin and irinotecan for evident locally advanced gastric cancer showed acceptable resection rate and local control, the overall prognosis was limited in this setting.
Clinical outcome of endoscopic submucosal dissection versus surgery for patients with early gastric cancer.
Authors: Shim Ki-Nam , Chang Ji Young , Tae Chung Hyun , Son Hyo Moon , Lee KoEun , Ryu Min Sun , Moon Chang Mo , Kim Seong-Eun , Jung Hye-Kyung , Jung Sung-Ae , Lee Joo-Ho
Published: February 2017

15

Background: This study aimed to compare the clinical outcomes of endoscopic submucosal dissection (ESD) and surgery for the patients with early gastric cancer (EGC). Methods: Data of 79 EGCs in 76 patients treated with ESD and 59 EGCs in 57 patients treated with surgery between 2005 and 2015 were analyzed retrospectively. We only included EGCs confined to the mucosal layer. Demographic data, pathologic data, complication, 5-year overall survival (OS) data were collected. Results: The clinicopathological characteristics of the patients were shown in Table 1. The mean follow-up periods were 31.5 months (5-96 months) for ESD group and 68.4 months (1-139 months) for surgery group (P < 0.001). One patient (1.9%) in ESD group has experienced metachronous tumor, but there was no patient who had recurrence tumor or metastasis in surgery group. The 5-year OS rates did not differ between two groups (91.2% in ESD group versus 87.4% in surgery group, respectively; P = 0.490 by log-rank test). The early complication rates happened within 3 months of procedure were similar in both groups (P = 0.501). However, the late complication rates were significantly higher in surgery group than those in ESD group (P = 0.002). Conclusions: The clinical outcomes after ESD including 5-year OS were comparable to those of surgery. Regarding the late complication, ESD was superior to surgery.
Small caliber covered self expanding metal stents in the management of malignant dysphagia.
Authors: Kucera Steven , Shridhar Ravi , Klapman Jason , Harris Cynthia L. , Hoffe Sarah E. , Barthel James S. , Almhanna Khaldoun , Meredith Kenneth
Published: February 2017

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Background: Use of large caliber ( ≥ 18 mm body diameter) self expanding metal stents (SEMS) for management of malignant dysphasia is associated with substantial adverse event (AE) and mortality rates (MRs). We sought to determine dysphagia response, stent migration rates, and AE and MRs, for small caliber covered SEMS (sccSEMS) with body diameters (BDs) between 10 - 16 mm in malignant dysphagia. Methods: We identified 31 patients underwent direct endoscopic placement of 50 sccSEMS. Patients were monitored for change in dysphagia score (DS), stent migration, AEs, and death. Results: The cohort consisted of 23 (74%) men and 8 (26%) women with a median age of 64 years (35 - 87 years). Esophageal adenocarcinoma (AC) was present in 19 (61%) patients and squamous cell carcinoma (SCCA) in 12 (39%) patients. Of the patients with SCCA, 2 tumors were located in the proximal esophagus, 7 in the mid-esophagus and 3 in the distal esophagus. All 19 ACs were located in the distal esophagus. The AJCC clinical stages at time of sccSEMS placement were: 1 (3%) Stage II, 8 (26%) Stage III, and 22 (71%) Stage IV. The initial pre-stent lumen diameter was less than 8 mm in 77% (24/31) of patients. The initial pre-stent lumen diameter was equal to 9 mm in 1 patient (3%), equal to 10 mm in 4 patients (13%), and equal to 11 mm in 2 patients (6%). The median pre-stent tumor length was 5.0 cm (interquartile range 4.0 – 7.0 cm). Dysphagia score improved in 30 of 31 patients (97%). The median DS decreased from 3 to 2 (p < 0.0001). The median effective duration of first sccSEMS placement was 116 (95% CI: 75-196) days. Major and minor AE rates were 6.5% and 19.4% respectively. No stent related deaths were encountered. The overall migration rate was 36% (18/50). The anticipated migration rate was 45.7% (16/35) and the unanticipated migration rate was 13.3% (2/15) (p = 0.052). Positive effective clinical outcome occurred in 93.5% (29/31) of cases. Conclusions: In malignant dysphagia, direct endoscopic sccSEMS placement provided acceptable dysphagia control and migration rates with substantial reductions in stent related AEs and MRs compared to those reported for large caliber SEMS.
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

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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

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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

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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

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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.
A novel pathology-based preoperative risk score to predict distant and locoregional residual disease and survival for incidentally discovered gallbladder cancer: A 10-institution study from the US Extrahepatic Biliary Malignancy Consortium.
Authors: Ethun Cecilia Grace , Postlewait Lauren McLendon , Pawlik Timothy M. , Buettner Stefan , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Jin Linda , Weber Sharon M. , Salem Ahmed I. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar
Published: February 2017

202

Background: T-stage alone is currently used to guide treatment for incidentally discovered gallbladder cancer. We aimed to develop a more robust predictive model for discovering distant or locoregional residual disease at the time of re-resection. Methods: All patients with incidentally discovered gallbladder cancer who underwent re-resection at 10 institutions from 2000-2015 were included. We utilized routine pathology data from initial cholecystectomy to create a gallbladder cancer predictive risk score (GBRS) for finding distant or locoregional residual disease at re-resection and predicting overall survival (OS). Results: Of 449pts with gallbladder cancer, 262 (58%) were incidentally discovered and underwent attempted re-resection. Advanced T-stage, grade, and lymphovascular (LVI) and perineural (PNI) invasion were all associated with increased rates of distant and locoregional residual disease, and decreased OS. Each pathologic characteristic was assigned a value (T1a: 0, T1b: 1, T2: 2, T3/4: 3; well diff: 1, mod diff: 2, poor diff: 3; LVI neg: 1, LVI pos: 2; PNI neg: 1, PNI pos: 2), which were added for a total GBRS score ranging from 3-10. The scores were then separated into 3 risk groups (Low: 3-4; Intermediate: 5-7; High: 8-10). Each progressive GBRS group was associated with an increased risk of finding distant and isolated locoregional residual disease at the time of re-resection, and was associated with reduced median OS (Table). Conclusions: By accounting for pathologic variations within each T-stage, this novel predictive risk-score redistributes T1b, T2, and T3 disease across separate risk-groups and more accurately identifies patients with incidentally discovered gallbladder cancer at risk for distant and locoregional residual disease, and decreased long-term survival. This score may help to better optimize treatment strategy for patients with incidentally discovered gallbladder cancer. [Table: see text]
Molecular diagnosis with the 92-Gene Assay (92-GA) and decision-impact on treatment: Final results from a prospective, multi-disciplinary study.
Authors: Thomas Sachdev P. , Braiteh Fadi S. , Jacobson Lauren , Victorio Anthony R. , Cherkis Karen Ann , Operana Theresa N. , Blatner Nichole Renee , Schroeder Brock , Schnabel Catherine A.
Published: February 2017

205

Background: Metastatic lesions with unknown or differential diagnoses pose significant challenges leading to suboptimal treatment and outcomes. Molecular diagnosis with the 92-GA has shown improved accuracy compared to IHC and improved survival in pts treated based on assay results. The following prospective, multi-institutional study assessed the utility and impact of the 92-GA in diagnosis and treatment decision-making in community clinical practice. Methods: Over 18 months, physicians (68 medical oncologists, 25 pathologists) completed standardized, discipline-specific questionnaires via a web-based data portal for 444 cases in which the 92-GA was ordered as part of routine clinical care for pts with unknown or differential diagnoses. Physician-reported utility and impact were characterized for oncologists and pathologists. Results: 92-GA molecular diagnoses included 22 different tumor types: pancreaticobiliary (21%), lung squamous (9%), lung adenocarcinoma (9%), and intestinal (9%) were most common. Factors contributing to ordering the 92-GA were interdisciplinary: for oncologists, no primary following clinical review and imaging (42%), pathology report of a differential diagnosis (21%) or unknown primary (20%), and differentiation between a new cancer or recurrence (16%) were most common; for pathologists, IHC inconclusive (50%; median 9 IHC stains) and oncology ordered due to unknown primary (30%) were most common. Oncologists reported that the diagnosis provided by the 92-GA resulted in changing the treatment option in 46% of cases. 75% of pts received therapy with a median time from biopsy to treatment of 25d. Following the 92-GA, predictive biomarkers (eg, EGFR, ALK) were ordered in 81% of cases diagnosed as lung and 67% diagnosed as colorectal cancer. Conclusions: This study demonstrated significant clinical utility of the 92-GA: changing treatment options in approximately half of pts. Clinical utility spanned a spectrum of diagnostic uncertainty for oncologists and pathologists, and helped narrow differential diagnosis. Additional biomarker testing was common after a diagnosis of lung or colorectal cancer was rendered by the 92-GA.
Identification of prognostic value of lymphocyte-to-monocyte ratio in patients with advanced HBV-associated hepatocellular carcinoma.
Authors: Chen Zhan-Hong , Hong Yingfen , Ma Xiao-kun , Li Xing , Wu Dong-hao , Lin Qu , Dong Min , Chen Jie , Wei Li , Wang Tian-tian , Ruan Dan-yun , Wen Jingyun , Wu Xiang-yuan
Published: February 2017

206

Background: Inflammatory microenvironment plays an important role in the progression of HCC. Peripheral blood LMR, as a novel inflammatory biomarker combining an estimate of host immune homeostasis and tumor microenvironment, has been found to be a predictor for clinical outcomes in various malignancies. There have been no reports regarding the prognostic value of LMR in advanced HCC until now. We want to investigate the prognostic value of LMR in patients with advanced HBV-associated hepatocellular carcinoma. Methods: From September 2008 to June 2010, a total of 174 patients with HBV-associated advanced HCC without fever or signs of infections were analyzed. Clinicopathological parameters, including LMR, were evaluated to identify predictors of overall survival. Univariate and multivariate analyses were performed, using the Cox proportional hazards model. The best cutoff was determined with time-dependent receiver operating characteristic curve. Results: Univariate and multivariate analyses showed that LMR was an independent prognostic factor in overall survival in patients with advanced HCC(P < 0.01 ). The best cutoff point of LMR was 4.52. All patients were dichotomized into either a low LMR group( ≤ 4.52) or a high LMR group( > 4.52). Overall survival(OS) of high LMR group was significantly longer than that of low LMR group(P < 0.01 ). High LMR group patients had significantly higher 6-month OS rate(50% vs 23%, P < 0.01) than that of low LMR group patients. Higher LMR level was significantly correlated with the presence of metastasis and larger tumor size(P < 0.05). Conclusions: LMR is an independent prognostic factor of advanced HCC patients. Higher Baseline LMR levels indicates better prognosis.
Age barrier in clinical trials: Are we truly moving forward?
Authors: Ayodele Olubukola , Linkeviciute-Koneko Aiste , O'Connor Miriam , Calvert Paula , Horgan Anne M.
Published: February 2017

208

Background: Older patients are underrepresented in clinical trials. This may in part be explained by the fact that, historically, there has often been an upper age limit for inclusion in studies. This is despite data that suggests that older patients are as likely as their younger counterparts to enroll in clinical trials if offered. Methods: All prospective, interventional phase III studies in GI malignancies registered with clinicaltrials.gov were identified. Currently opened and recruiting studies were included. Results: A total of 365 eligible trials were identified. One hundred and fifty (41%) were colorectal, 67 (18%) liver and 62 (16%) were pancreatic malignancies. Other malignancies were gastroesophageal, hepatobiliary and neuroendocrine tumours. A total of 172 (47%) studies had an upper age limit for inclusion. The most common tumor sites to have older age as an exclusion factor were - hepatobiliary (n = 10; 66%), liver (n = 39; 58%) and gastroesophageal (n = 31; 51%). The median age of exclusion was 75 years (range: 60-95). Chinese studies, which represented 30% (n = 111) of the total studies included, had the greatest proportion with an upper age limit (85%). The United States had the least, with only 3% of studies having an exclusion age. Conclusions: Significant progress had been made in recent years with many clinical trial protocols not having an upper age limit for inclusion. Study design and restrictive eligibity criteria need to be assessed and modified to ensure older patients are well represented in future clinical trials.
Does metabolic tumor volume predict tumor regression grade after neoadjuvant therapy for borderline resectable pancreatic cancer?
Authors: Jin Will , Mellon Eric Albert , Hoffe Sarah E. , Frakes Jessica M. , Springett Gregory M. , Hodul Pamela Joy , Centeno Barbara , Kim Richard D. , Mahipal Amit , Pimiento Jose Mario , Malafa Mokenge Peter , Latifi Kujtim
Published: February 2017

214

Background: Metabolic tumor volume (MTV) based on FDG-PET has been shown to be prognostic for overall survival (OS) in patients with resectable, borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). Tumor regression grade (TRG) following neoadjuvant therapy has also been shown to correlate with OS. No data currently exists evaluating whether metabolic response defined by MTV can predict pathologic response in BRPC. Methods: This IRB approved retrospective review evaluated 40 non-metastatic BRPC patients. All patients underwent staging imaging including FDG PET/CT. They then received induction multi-agent chemotherapy followed by five fraction stereotactic body radiation therapy (SBRT) with a median maximum dose of 35 Gy. Repeat pre-operative FDG PET/CT was performed for re-staging. Patients then underwent pancreatectomy. For this study, the diagnostic images were transferred to a software system that analyzed the pre-treatment, re-staging, and change in (differential) MTV values. We analyzed SUVmax and each of MTV2.5, MTV3.0, MTV4.0, and MTV5.0, as defined as the tumor volume with SUV above each threshold. At our center, each surgical specimen is assigned TRG using the College of American Pathology (CAP) criteria. The TRG scores regression from 0 – 3, with 0 indicating complete response and 3 indicating no response. Univariate ordinal logistic regression was used to correlate TRG with pre-, post-, absolute differential, and percent differential MTV 2.5-5.0 and SUVmax. Results: Of the sample population, TRG was as follows: TRG 0 n = 4, TRG 1 n = 17, TRG 2 n = 14, TRG 3 n = 5. TRG correlated with rradiologist reported re-staging SUVmax (p = 0.001) and percent differential SUVmax (p = 0.044). TRG did not correlate with pre-treatment SUVmax, absolute differential SUVmax, or any MTV measurements (all p > 0.05). Conclusions: We identified a correlation between SUVmax and percent change in SUVmax after neoadjuvant therapy with TRG (CAP scale). This analysis did not identify an association between any MTV threshold and TRG before or after neoadjuvant therapy. Future work seeks to identify alternate methods of neoadjuvant response assessment.