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IntroductionStandard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation.MethodsA total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated.ResultsOf the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities.ConclusionsIn our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

Background Efficacy of immune checkpoint inhibitors (ICIs) in metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma is inconsistent. Whether the efficacy of ICIs is comparable across different subgroups remains unknown. Methods We identified randomized controlled trials (RCTs) that compared standard treatment for metastatic gastric/GEJ adenocarcinoma to ICIs. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta‐analysis. Prespecified subgroups were included as follows: age at randomization (65 years), gender (female vs male), ethnicity (Asians vs non‐Asians), performance‐status (0 vs 1), tumor location (gastric vs GEJ), and histological subtype (diffuse vs others). OS in patients with programmed death ligand (PD‐L1) positive and with microsatellite instability‐high (MSI‐H) were also extracted and pooled in a meta‐analysis. Results Five RCTs comprising 2,264 patients were analyzed. Compared to standard therapy, ICIs did not improve OS (HR = 0.86, 95% CI 0.71‐1.03, P = .10) and the effect of ICIs on OS was similar in all subgroups. Nonsignificantly greater effect sizes were seen in older patients (HR = 0.85 vs 0.88, P = .81), male (HR = 0.82 vs 0.99, P = .16), Asians (HR = 0.86 vs 0.96, P = .55), performance‐status 0 (HR = 0.84 vs 0.88, P = .81), GEJ tumors (HR = 0.78 vs 0.90, P = .37), and nondiffuse subtype (HR = 0.71 vs 0.79, P = .62). ICIs were associated with significantly improved OS in patients with MSI‐H (HR = 0.33, P = .001), but not in PD‐L1 positive disease (HR = 0.86, P = .06). Conclusions Compared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups has shown increased magnitude of effect to ICIs, aside of the small group with MSI‐H tumors., Compared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups including, age, gender, ethnicity, performance status, primary tumor location, and histological subtype, has shown increased magnitude of effect from ICIs. In exploratory analysis for small group with MSI‐H tumors, treatment with ICIs was associated with significant OS improvement compared to the control group.

BACKGROUND Esophageal cancer represents a global challenge. Despite significant evolution of treatment protocols in the past decade, recurrence rates are still high and survival rates are poor. Current treatment paradigm for localized gastroesophageal junction (GEJ) carcinoma remains to be further elucidated as for the role of neoadjuvant chemoradiation versus perioperative chemotherapy. AIM To identify biomarkers for response to chemoradiation in esophageal and gastroesophageal cancer, we performed an in-depth proteomic analysis of esophageal and gastroesophageal tumors, to describe differences in pathway activation between patients with favorable and poor prognosis following neoadjuvant chemoradiation. METHODS Patients with locally advanced esophageal and gastroesophageal cancer following neoadjuvant chemoradiation were included in the cohort. The study cohort was dichotomized into two groups of patients, named "favorable prognosis" and "poor prognosis" according to the postoperative disease-free interval. We performed a mass spectrometry analysis of proteins extracted from the malignant regions of surgical specimens and analyzed data from electronic medical records. Clinical data was correlated with differences in protein expression between patient with a favorable and poor prognosis using validated gene expression pathways. RESULTS The study included 35 patients with adenocarcinoma. All patients in this cohort had esophageal adenocarcinoma. Patients median age was 62 years. Twenty-five (71.3%) patients underwent neoadjuvant chemoradiation, and 28.7% underwent neoadjuvant chemotherapy only. A proteomic analysis of our cohort identified 2885 proteins. Enrichment levels of 98 of these proteins differed significantly between favorable and poor prognosis cohorts in patients who underwent neoadjuvant chemoradiation (p

To determine whether the expression of specific molecular markers in the rectal cancer biopsies prior to treatment, can correlate with complete tumor response to chemoradiotherapy (CRT) as determined by the pathology of the surgical specimen.We retrospectively examined pretreatment rectal biopsies of patients aged 18 years or older with locally advanced rectal cancer who had been treated with neoadjuvant CRT and surgical resection in our tertiary-care, university-affiliated medical center, between January 2001 and December 2011. Samples were analyzed for expression of B-cell lymphoma 2, P53, Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, and the tumor regression grade after CRT and radical surgery.Forty-seven patients were included in the final analysis. Main outcome measures were the correlation between the expression of the molecular markers tested in the pretreatment biopsy, and complete tumor response. Complete pathologic response after CRT was attained in 27% of the patients. Percentage of cells expressing EGFR in the pretreated biopsies of patients having complete pathologic response after CRT and surgery was 33.08±7.87% compared to 19±15.36% (P=0.38), 6.66±2.83% (P0.003), and 12.5±4.93% (P=0.033) in patients with partial response and tumor regression grades of 2, 3, and 4, respectively. The other molecular markers tested in the pretreatment biopsy did not corresponded with complete pathologic response.EGFR expression pattern in the pretreatment biopsies of rectal tumors can assist in identifying patients who will benefit from neoadjuvant CRT.

6518 Background: Preoperative long-course chemoradiotherapy (CRT) and short-course radiotherapy (SCR) for locally advanced rectal cancer (LARC) were found to have equivalent outcomes in three randomized trials. SCR may have lower acute toxicity and the down-staging following CRT is more well-established. At present, SCR is frequently used in Europe but has not been widely adopted in the United States (US). It is standard to deliver radiotherapy by 3D planning, while the use of Intensity-modulated radiotherapy (IMRT) is controversial. In recent years there has been an increasing focus on understanding the cost and value of cancer care. In this study we aimed to assess the economic impact of fractionation scheme and treatment planning method for payers in the US. Methods: We performed a population-based analysis of the total cost of radiotherapy for LARC in the US annually. The national annual target population of patients was calculated using the Surveillance, Epidemiology, and End Results (SEER) database. Treatment costs for various fractionation schemes were based on billing codes and 2018 pricing by Medicare's Hospital Outpatient Prospective Payment System (OPPS). The cost of chemotherapy was based on the Payment Allowance Limits for Medicare Part B Drugs by Centers for Medicare and Medicaid Services (CMS). Results: We estimate that 12,945 patients with LARC are treated with radiotherapy annually in the US. The cost of CRT with 3-D or IMRT is US$ 15,881.76 and US$ 23,744.82 per patient, respectively. With 3-D SCR the cost is US$ 5,457 per patient. The use of SCR would lead to 64-77% annual savings of US$ 125,701,387 - US$ 236,727,934 in the US compared with 3-D and IMRT based CRT, respectively. IMRT based planning increases the total cost of CRT by 49% and if adopted widely would lead to an excess cost of US$ 101,787,312 annually. Conclusions: SCR may have the potential to save in the region of US$ 0.12-0.23 billion annually in the US, likely without impacting outcomes. Lack of evidence showing benefit with costly IMRT should limit its use to clinical trials. SCR may also lead to lower personal financial toxicity. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement.

e15599 Background: A substantial number of pts with pathological stage III CC recur despite the absence of metastatic disease on pre-operative CT. In a previous large retrospective study from our institution on 348 pts, we reported that early postoperative PET-CT modified the staging and management of 13.4% of assumed stage III CC pts. The aim of the current study was to prospectively validate these results. Methods: A prospective, single-center study of pts with pathological stage III CC who underwent early postoperative PET-CT between the years 2013-2021. Results: 83 pts were accrued and 81 (48.1% males, median age 66y) were evaluable for the primary endpoint i.e. PET-CT results. Pathological stage was IIIA, IIIB and IIIC in 7 (8.6%), 56 (69.1%) and 17 (21%) of pts, respectively. Median number of lymph nodes examined and of positive nodes were 17 (range, 9-134) and 2 (range, 0-15), respectively. Post-operative PET-CT findings were significant in 7 pts (8.6%): 4 pts (4.9%) were upstaged to stage IV, 2 (2.5%) were diagnosed with a second primary malignancy, and 1 (1.2%) was both upstaged and diagnosed with another cancer. Three additional pts (3.7%) are currently undergoing evaluation for suspicious PET-CT findings. At a median follow-up of 30.6 months (range, 6.2-92), 13 of the 71 pts with true stage III CC recurred; the estimated 3y disease-free survival rate was 81%. The estimated 5y overall survival rates for the entire cohort and for true stage III pts were 82% and 90%, respectively. Of the 5 pts found to have metastatic disease based on PET-CT findings, one is scheduled to undergo potentially curative surgical removal of a solitary liver metastasis. Conclusions: Interim results from the first prospective study to evaluate the impact of early postoperative PET-CT in pts with pathological stage III CC seem to support earlier retrospective data: the use of PET-CT in this setting changed the staging and management of 8.6% of pts, including the possibility for early detection of potentially curable metastatic disease. Additional data, with more pts and longer follow-up, will be presented at the meeting.

e16587 Background: Patients with metastatic gastric or GEJ cancer have short duration of response to chemotherapy and poor outcome. Treatment with ICIs has been investigated for this population with inconsistent results. It is uncertain whether the effect of ICIs is comparable in different subgroups. Methods: Randomized controlled trials (RCTs) that compared standard treatment to treatment with ICIs, either as a monotherapy or in combination with chemotherapy, for metastatic gastric or GEJ cancer were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta-analysis using generic inverse variance and random effects modelling. Pre-specified subgroups included: patients’ age at time of randomization (age < /≤ 65 years versus ≥/ > 65 years), gender (female versus male), ethnicity (Asians versus the rest of the world), Eastern Cooperative Oncology Group performance status (0 versus 1), primary tumor location (gastric versus GEJ) and histological subtype (diffuse versus other subtypes). Data on progression free survival (PFS) and on OS in patients with programmed death ligand (PDL1) positive were also collected. Results: Four RCTs comprising 1,765 patients were analyzed. Treatment with ICIs compared to standard therapy did not significantly improve OS (HR = 0.84, 95% CI 0.66-1.07, p = 0.17), PFS (HR = 1.22, 95% CI 0.75-1.96, p = 0.52), or OS in patients with PDL1 positive disease (HR = 0.86, 95% CI 0.73-1.02, p = 0.08). The effect of ICIs on OS was similar in all subgroups. Non-significantly greater effect sizes were seen in younger patients (HR = 0.82 versus 0.86, p for subgroup difference 0.80), male (HR = 0.81 versus 0.97, p = 0.32), performance status 0 (HR = 0.84 versus 0.88, p = 0.81), GEJ tumors (HR = 0.76 versus 0.89, p = 0.44) and non-diffuse subtype (HR = 0.71 versus 0.79, p = 0.62). Conclusions: Compared to standard treatment, ICIs in metastatic gastric or GEJ cancer did not improve OS significantly. As none of the evaluated subgroups has shown increased magnitude of effect to ICIs, other biomarkers for ICIs response are desired in order to optimize the risk versus benefit balance of these patients.

AIM This phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiotherapy (CRT) in locally advanced esophageal cancer (LAEC). METHODS Patients (pts) with resectable LAEC (T2-3N0-1M0, T1-3N1M0 or T1-3N0-1M1A) received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-fluorouracil (5-FU) 1000 mg/m2/day, days 1-5, followed 4 weeks later by radiotherapy, 50.4 Gy, given with 2 cycles of cisplatin 75 mg/m2 and escalating doses of 5-FU, days 1-4 and 29-32. Pts received 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose, 400 mg/m2. Surgery was planned 6-8 weeks after CRT. RESULTS 64 pts were treated and 60 completed CRT. Median age was 65 years and 66% were males. Adenocarcinoma/squamous ratio was 61%/39%. Tumors were advanced: 95% T3 and 67% N1. Grade ≥3 toxicities occurred in 72%, with two (3%) toxic deaths. The 5-FU maximal tolerated dose (MTD) was 1000 mg/m2/day. Clinical complete response rate was 33%. Of the 55 operated pts, R0 resection was achieved in 51 (93%) and pathological complete response (pCR) in 18 (33%), with 8 (14%) postoperative deaths. The 5-year survival rate for all pts was 38%. Pts with squamous histology had higher pCR (55% vs 20%, p = 0.015), local control (96% vs. 74%, p

Background Current staging of pathological stage III colon cancer (CC) is suboptimal; many patients recur despite unremarkable preoperative staging. We previously reported that early postoperative PET‐CT can alter the stage and management of up to 15% of patients with high‐risk stage III CC. This study aimed to determine the role of the test in the general stage III CC population. Methods A retrospective study of all consecutive patients with stage III CC who underwent early postoperative PET‐CT between 2005 and 2017. Results A total of 342 patients, 166 (48.5%) males, median age 66 years (range, 29‐90), were included. Pathological stage was IIIA, IIIB, and IIIC in 18 (5.3%), 257 (75.1%), and 67 (19.6%) patients, respectively. Median number of positive lymph nodes was 2 (range, 0‐32). PET‐CT results modified the management of 46 patients (13.4%): 37 (10.8%) with overt metastatic disease and 9 (2.6%) with a second primary. The 5‐year disease‐free survival for true stage III patients was 81%. The median overall survival for the entire cohort and for true stage III patients was not reached and was 57.2 months for true stage IV. Of the 37 patients found to be metastatic, 14 (37.8%) underwent curative treatments and 9/14 (64.3%) remain disease‐free, with a median follow‐up of 83.8 months. Predictive factors for upstaging following PET‐CT were identified. Conclusion Early postoperative PET‐CT changed the staging and treatment of 13.4% of stage III CC patients and has the potential for early detection of curable metastatic disease. Outcome results are encouraging. Prospective validation is ongoing.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011–2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1–9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

Background and Purpose Stereotactic body radiotherapy (SBRT) is an emerging modality for definitive treatment of Hepatocellular carcinoma (HCC). Materials and Methods This retrospective study included all early stage HCC patients who were not candidates for primary resection and/or local therapy, treated with SBRT between 11/2011 and 1/2016. Results Twenty-three patients were included. The median age was 62 years; 70% males; 30% females; 70% viral hepatitis carriers; 100% cirrhotic; 13 Child Pugh [CP]-A and 10 [CP]-B. The median tumor volume was 12.7cm3 (range, 2.2–53.6 cm3). Treatment was well tolerated. With the exception of one patient who developed RILD, no other patient had significant changes in 12 weeks of laboratory follow-up. SBRT was a bridge to transplantation in 16 patients and 11 were transplanted.. No surgical difficulties or complications were reported following SBRT, and none of the transplanted patients had local progression before transplantation. The median prescribed dose to the tumor was 54Gy (range, 30-54Gy), the median dose to the uninvolved liver was 6.0Gy(range, 1.6–12.6Gy). With a median follow-up time of 12 months, the median overall-survival for the 11 transplanted patients was not reached (range, 2.0–53.7+ months) and was 23 months for the 12 non-transplanted patients. The median progression-free survival for the transplanted patients was not reached (54+ months) and was 14.0 months for the non-transplanted patients. There was no SBRT-related mortality. Liver explant post SBRT revealed pathological complete response in 3(27.3%), pathological partial response in 6(54.5%), and pathological stable disease in 2(18.2%) tumors. Conclusions SBRT is safe and effective and can be used as a bridge to transplantation without comprising the surgical procedure.

Introduction: Data regarding esophageal cancer (EC) in Israel are limited. The aim of this study was hence to characterize this entity in the Israeli population and to compare it to the literature. Patients/Methods: This is a retrospective study of all consecutive EC patients treated at our institution between 1997-2013. Data were retrieved from patients' medical files. Results: Two hundred patients were included. The median age at diagnosis was 70.5 years; 63.5% were males; 63% were Ashkenazi Jews, 29% were Sephardic Jews, and 0.5% were Arabs. Squamous cell carcinoma (SCC) was predominant: 52% versus 45.5% with adenocarcinoma (ADC). SCC was common even in the distal esophagus (45%). The overall 5-year survival rate was 25.5%. A temporal trend (2006-2013 vs 1997-2005) shows a decline in the proportion of SCC (47% vs 63%, p=0.061) and a rise in ADC (50% vs 33%, p=0.041), with a parallel decrease in patients' age (median: 68.5 vs 73 years, p=0.014). In the later period, patients received more treatment for localized and metastatic disease, with a trend for improved median survival (20.1 vs 14.9 months, p=0.658). Ashkenazi Jews were diagnosed at an older age than Sephardic Jews (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI cancer (34% vs. 17%, p=0.026) and a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041). Conclusion: EC in Israel represents an intermediate entity between the Western and the endemic subtypes, showing some unique features. These included delayed reversal of the SCC/ADC ratio, commonness of SCC in the distal esophagus, prevalence of other malignancies and predominance of Ashkenazi ethnicity. The reason for these findings is unclear and its further evaluation is warranted.

61 Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery represents a key therapeutic strategy for locally advanced esophageal cancer (LAEC). Former studies addressed the clinicopathological patterns of patients who demonstrated good response to NCRT compared with inferior response. Nevertheless, there is paucity of data regarding potentially involved cellular pathways that account for tumor response to NCRT. We performed a comprehensive proteomic analysis to identify the key differences in protein function and pathway activation between patients with a poor response and those with a favourable response to treatment. Methods: Patients diagnosed with LAEC who were treated with NCRT and operated at our institution were included in the study. Patients were defined as good responders (GR) upon the tumor regression grade (TRG) in the pathological specimen: GR defined as TRG 0/1 and no evidence of recurrence at 1-year post surgery. Bad responders (BR) were defined as TRG 2/3 and recurrence < 1year. Tumor was isolated from the surgical specimen and proteins were extracted and processed for mass spectrometry-based analysis. Clinical data of demographics, response to treatment, and survival was retrieved from electronic medical records. Difference in protein expression between GR and BR were analysed using validated gene expression pathways tools and correlated to clinical data. Results: Forty-four patients were included in the cohort. Mean age was 66.7 years, male predominance (33/44). Thirty-five patients had adenocarcinoma – 17 GR and 18 BR. Nine patients had squamous cell carcinoma – 6 GR and 3 BR. Protein expression patterns significantly differed between GR and BR regardless of histology, mainly in cellular pathways account for nucleic acid metabolism (p < 10-9), whereas BR had overexpression of these genes. Conclusions: Our study indicate that lack of response to NCRT may derive from overexpression of unique cellular pathways. Former studies imply these cellular pathways may play a role in resistance to cisplatin. Larger transcriptomic studies are warranted for future analysis to extend these observations.

Purpose Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of 18F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT).

The addition of docetaxel to cisplatin and 5-fluorouracil was shown to confer a survival benefit in patients with advanced gastric cancer (one; AGC), although with increased toxicity. We hereby report our experience with the use of docetaxel, cisplatin, and 5-fluorouracil (DCF). Data on all consecutive patients who received first-line treatment with DCF at our institute were analyzed retrospectively. Twenty-three patients were included. The median age was 63 years. Patients received an average of 10 cycles (range, 1-24). All experienced grade ≥3 toxicity, requiring hospitalization in 35%. There was one toxic death. The median progression-free and overall survival rates were 10.0 and 12.8 months, respectively; the 2-year and 3-year survival rates were 22 and 17%, respectively. The DCF regimen is indeed associated with substantial toxicity, although manageable. Nevertheless, the observed benefit was remarkable compared with any previous report on chemotherapy in AGC, and should therefore represent a valid treatment option in AGC and a platform for future combinations.

Background: We investigated the efficacy and tolerability of cisplatin and 5-fluorouracil (5-FU) plus bevacizumab as neoadjuvant therapy for patients with locally advanced resectable esophageal cancer. Patients and Methods: In this prospective phase II study, 22 patients with adenocarcinoma and 6 with squamous cell carcinoma received 2 4-day cycles of bevacizumab 7.5 mg/kg followed by cisplatin 80 mg/m2 infusion on day 1 followed by 5-FU 1,000 mg/m2 as a 96-h continuous infusion on days 1–4, separated by a 3-week interval. Results: The response rate was 39%, the R0 resection rate was 43%, and the median overall survival (OS) was 17 months. The regimen was well tolerated, with the most common severe toxicities being venous thromboembolism (10%), nausea, and gastrointestinal bleeding (7% each). In 37 patients previously treated with cisplatin and 5-FU alone at our institution and thus serving as historical controls, the response rate was 30%, the R0 resection rate was 44%, and the median OS was 23 months. There was no statistically significant difference between the 2 groups of patients. Conclusion: Adding bevacizumab to cisplatin and 5-FU neoadjuvant chemotherapy was active and well tolerated but did not seem to improve the resection rate or OS compared with prior regimens, including the historical controls at our institution.

Introduction Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part). Results The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5-52.2 months) and the median progression-free survival was 7.6 months (range, 1.3-26.6 months). The 2-year OS rate reached 23.7%. Conclusions AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients. Trial registration ClinicalTrials.gov NCT00845884.

Background Gastric cancer (GC) in Israel remains incompletely characterized. The aim of this study was to define the clinical and pathological characteristics of GC in Israel and to compare them to the general Western population. Patients and Methods This is a retrospective analysis of 461 consecutive GC patients treated at a single institution between 1995 and 2007. Epidemiological and clinical-pathological data were retrieved from the patients' medical files and the institutional electronic database and analyzed using standard statistical methods. Results Epidemiology, clinical manifestations, histopathological findings, clinical course, and prognostic factors for disease outcome were all similar to those reported in the Western literature. Findings unique to the Israeli population included: (1) rarity of GC-associated risk factors; (2) increased GC incidence in Ashkenazi Jews; (3) high incidence of second primary malignancy and family history of cancer; and (4) no dominancy of proximal GCs. Conclusion There do not appear to be any major differences in the biology or clinical manifestations of GC in Israel. Western recommendations for diagnosis and treatment of GC may therefore be applied to the Israeli patient population. J. Surg. Oncol. 2012; 105:316–322. © 2011 Wiley Periodicals, Inc.

836 Background: Treatment of metastatic colorectal cancer (mCRC) has greatly advanced over the past decade, based on data from randomized controlled trials (RCTs). This raises the question whether results of RCTs, performed on selected patients (pts), do reflect outcomes in real-life practice. The aim of this study was to summarize our experience in the treatment of mCRC and compare it to data reported in RCTs. Methods: A retrospective single-institution study on consecutive mCRC pts treated with first-line bevacizumab-containing regimens in our institute between 2006 and 2014. Results: The study included 300 pts, of whom 54% were males. Median age was 67 years (range 28-90), 26% aged ≥ 75 years. ECOG performance status was ≤1 in 93%. The primary tumor site was right colon in 37%, left colon in 40%, rectal in 23% and 1% of pts had synchronous tumors. RAS status was available in 60%, of whom 55% had wild-type alleles. 46% of pts had a single metastatic site, including 27% with liver-limited disease, and 54% had multiple metastatic sites. Irinotecan-based chemotherapy was used in 66%, oxaliplatin-based chemotherapy in 29% and flouropyrimidine monotherapy in 5%. Curative metastasectomy during 1st line treatment was performed in 29%. Grade ≥3 hematological and non-hematological toxicities were reported in 24% and 38% of pts, respectively. Second and third line treatments were administered to 75% and 66% of pts, respectively; 73% of pts received both irinotecan and oxaliplatin through their treatment course and 76% of those with wild-type RAS were treated with anti-EGFR therapy. Overall response rate and disease control rate were 69% and 89%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 17 and 28 months, respectively. In a sub-group analysis on "RCT-like population", excluding pts ≥ 75 years, ECOG PS ≥ 3 and/or mutated/unknown RAS status, median PFS and OS were 15 and 29 months, respectively. Conclusions: The results of this study suggest that, if adhered to international clinical guidelines, outcomes reported in RCTs are indeed reproducible in routine clinical practice in unselected real-life pts. Additional data, with more pts and longer follow-up, will be presented.

Aims and Background To analyze the efficacy and toxicity of adjuvant chemotherapy followed by whole abdominal irradiation in the treatment of resectable gastric cancer with positive lymph nodes. Methods and Study Design Between 1996 and 1999, 10 patients with node-positive gastric cancer underwent complete gross resection and were treated by postoperative chemoradiotherapy. The chemotherapy regimen consisted of 5-fluorouracil, 1000 mg/m2/day as a 96-hr continuous infusion on day 1, and cisplatin, 100 mg/m2 on day 2, every 21 days. Six courses were planned. Radiotherapy was administered 3 weeks after completion of the chemotherapy protocol as a single-fraction dose of 600 cGy in a two-field (anterior and posterior) configuration. Results Treatment was generally well tolerated, with no treatment-related deaths. However, 9 of the 10 patients died of recurrent disease, with a median survival of 20 months (range, 7–84). Conclusions Adjuvant chemotherapy with whole abdominal irradiation for gastric cancer is safe and tolerable but has no apparent effect on patient outcome. Studies in larger series are needed to evaluate the role of the approach in this disease.

The incidence of colorectal cancer in young patients is increasing. It remains unclear if the disease has unique features in this age group.This was a single-center, retrospective cohort study which included patients diagnosed with colorectal cancer at age ≤40 years in 1997-2013 matched 1:2 by year of diagnosis with consecutive colorectal cancer patients diagnosed at age50 years during the same period. Patients aged 41-50 years were not included in the study, to accentuate potential age-related differences. Clinicopathological characteristics, treatment, and outcome were compared between groups.The cohort included 330 patients, followed for a median time of 65.9 months (range 4.7-211). Several significant differences were noted. The younger group had a different ethnic composition. They had higher rates of family history of colorectal cancer (p = 0.003), hereditary colorectal cancer syndromes (p 0.0001), and inflammatory bowel disease (p = 0.007), and a lower rate of polyps (p 0.0001). They were more likely to present with stage III or IV disease (p = 0.001), angiolymphatic invasion, signet cell ring adenocarcinoma, and rectal tumors (p = 0.02). Younger patients more frequently received treatment. Young patients had a worse estimated 5-year disease-free survival rate (57.6 vs. 70 %, p = 0.039), but this did not retain significance when analyzed by stage (p = 0.092). Estimated 5-year overall survival rates were 59.1 and 62.1 % in the younger and the control group, respectively (p = 0.565).Colorectal cancer among young patients may constitute a distinct clinical entity. Further research is needed to validate our findings and define the optimal approach in this population.

PURPOSE PET/CT may contribute to staging modification in different phases of colorectal cancer (CRC) management. However, it is not routinely indicated for stage III CRC. This study sought to determine the role of early postoperative PET/CT in patients with high-risk stage III CRC. PATIENTS AND METHODS The tumor registry of a tertiary medical center was searched (2004-2011) for all patients with stage III CRC who underwent early postoperative PET/CT because of the presence of high-risk factors for systemic disease. Demographic and clinicopathological characteristics were compared between patients found/not found to have metastatic disease. RESULTS The cohort included 91 patients with a median age of 67 years (range, 29-90 years). Pathological FDG uptake was observed in 38 (41%). Of these, 14 (15% of the whole cohort) were upstaged with alteration of their treatment protocol, 10 (11%) had local postoperative changes, and 14 (15%) had false-positive findings. The sensitivity and specificity of PET/CT for detecting metastatic disease were 100% and 69%, respectively. Elevated postoperative carcinoembryonic antigen and CA-19.9 levels correlated with a positive PET/CT (P = 0.05 and P = 0.03, respectively). The median follow-up time was 34 months (range, 4-85 months). The estimated 5-year survival rate was significantly higher in patients with a negative than a positive scan (70% vs 42%, P < 0.0006). CONCLUSIONS Findings on early postoperative PET/CT may influence staging and treatment in 15% of selected patients with high-risk stage III CRC. Postoperative levels of carcinoembryonic antigen and CA-19.9 may serve as indications for PET/CT scanning in this setting. Prospective validation is warranted.

4057 Background: Current treatment results in locally advanced esophageal cancer (LAEC) are far from being satisfying. This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative CRT in this disease. Methods: Patients (pts) with potentially resectable LAEC (T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A) received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-FU 1000 mg/m2/day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy given concurrently with 2 cycles of cisplatin 75 mg/m2 and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose of 400 mg/m2, starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: 64 pts were enrolled and 60 completed CRT. Median age was 65 years (range: 38-84 years) and 66% were males. The SqCC/adenocarcinoma ratio was 39%/61% (25/39). Pts had very advanced tumors: 95% T3-T4, 67% N1 and 19% M1A. The most common grade > 3 toxicities were leucopenia (45% of pts) and neutropenia (41%). There were two cases (3%) of fatal toxicities (neutropenic sepsis and sudden death). Among the 55 operated pts, R0 resection was achieved in 51 (93%). There were 8 cases (14.5%) of postoperative mortality, due to infection (3 pts), esophageal leak (2), bleeding (2) and pulmonary insufficiency (1). Pathological down-staging was noted in 72% of pts and pathological complete response (pCR) in 33%. 5y-local control, progression-free survival (PFS) and overall survival (OS) rates for all pts were 94%, 40%, 39%, respectively. Pts with SqCC had a significantly higher pCR rate (52% vs 15%, p = 0.007), 5y-PFS (67% vs. 21%, p = 0.008) and 5y-OS (64% vs. 20%, p = 0.019). Conclusions: This study suggests that the addition of cetuximab to standard preoperative CRT is safe. R0, pCR, local control and long term PFS and OS rates in pts with SqCC tumors are encouraging. Further evaluation of this approach in this population seems warranted.

e15163 Background: Staging of patients (pts) with pathological stage III colon cancer (CC) is currently suboptimal; many pts still recur despite an unremarkable preoperative staging. We previously reported that early postoperative PET-CT can alter the stage and management of up to 15% of pts with high risk stage III CC and later reported also encouraging preliminary results in a larger cohort of consecutive pts with stage III CC, in which staging and management were altered in 14.5%. The aim of the current study was to expand the previous one to a larger cohort and to evaluate the actual impact of early postoperative PET-CT on pts outcome. Methods: A Retrospective study of all consecutive pts with stage III CC who were treated at our institution and underwent early postoperative PET-CT between 2007-2016. Demographic and clinicopathological data were retrieved. Statistical analyses were done using standard methods. Results: 348 pts, 166 (47.7%) males, with a median age of 66 years (range, 29-92), were included. Pathological stage was IIIA, IIIB and IIIC in 21(6%), 254 (73%) and 73 (21%) pts, respectively. The median number of lymph nodes examined and of positive ones were 14 (range, 3-54) and 2 (range, 0-32), respectively. High FDG-uptake was noted in 95 (27.3%) pts, including 23 (6.6%) with clear postoperative changes and 18 (5.2%) with a false positive uptake, of whom 6 underwent invasive diagnostic procedures. PET-CT results modified the management of 52 pts (14.9%) who were found to have true positive findings: 44 (12.6%) with overt metastatic disease and 8 (2.3%) with a second primary tumor. At a median follow-up of 45.6 months, the estimated 5y disease-free survival for true stage III pts was 81.9% and the 6y overall survival of the entire cohort was 76.4%. Interestingly, of the 44 pts found to be metastatic, 12 (27.3%) underwent curative treatments and 8 (66.7%) of those remain free of disease, with a median follow-up of 64.7 months. Conclusions: In this large cohort, early postoperative PET-CT changed the staging and management of 14.9% of pts with resected stage III CC, with encouraging outcome results. We are conducting a prospective trial to further evaluate this strategy.

552 Background: Colorectal cancer (CRC) in Octogenarians is an emerging clinical entity. It is currently unclear whether these patients have unique features and whether their treatment should differ from younger patients with CRC. The aim of this study was to better characterize this patients population. Methods: A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of ≥ 80 years between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Results: The study included 350 patients, followed for a median of 40.2 months (range 1.8-97.5). Several significant differences were noted. Elderly patients had a higher proportion of Ashkenazi ethnicity (p < 0.001), lower rates of family history of any cancer (p < 0.001) and family history of CRC (p = 0.006), and a higher rate of personal history of other malignancies (p = 0.035). CRC diagnosis by screening was less frequent in octogenarians (p < 0.001) and their performance status at presentation was worse. Octogenarians were more likely to have tumors located in the right colon (p = 0.029) and had a lower prevalence of well differentiated histology (p = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of performance status. Their 5-year cancer specific survival was worse (63.4% vs.77.6%, p = 0.009), both for metastatic (p = 0.03) and for non-metastatic disease (p = 0.028). Conclusions: Elderly patients with CRC presented several differences in clinical and tumor characteristics compared to their younger counterparts. They were less likely to receive treatment and they had worse outcome. Further research is needed to better define this growing patient population and to establish their optimal treatment.

562 Background: Current staging of patients (pts) with pathological stage III colon cancer is suboptimal; many pts still recur despite unremarkable preoperative staging work-up. We previously reported that early postoperative PET-CT can alter the stage and management of pts with high risk stage III colon cancer in up to 19% of patients. The aim of the current study was to expand the previous one to a larger cohort and to determine the role of early postoperative PET-CT in the general population of stage III colon cancer pts, regardless of their individual risk. Methods: A retrospective chart review of all consecutive pts with stage III colon cancer who underwent early postoperative PET-CT between 2007 and 2016. Demographic and clinicopathological data were collected. Results: 247 pts, 124 (50%) males, with a median age of 66 years (range, 30-92), were included. Pathological stage was IIIA, IIIB and IIIC in 18 (7.3%), 161 (65.1%) and 72 (29.1%) pts, respectively. The median number of lymph nodes retrieved was 15 (range, 6-64) and that of positive lymph nodes was 2 (range, 0-21). High FDG-uptake was observed in 52 (21.0%) pts, including 6 (2.4%) who had clear postoperative changes, 10 (4.0%) who had a false positive abnormal uptake of whom 6 underwent invasive diagnostic procedures. The PET-CT results modified the management of 36 pts (14.5%) who were found to have true positive findings: 30 (12.1%) were proven to have overt metastatic disease and in 6 (2.4%) a second primary was discovered. With the median follow-up of 39.0 months (range 7.2-98.4 months), of the 30 pts found to be metastatic, 10 (33.3%) underwent curative treatments and are currently with no evidence of disease (NED). Updated data, on more patients and a longer follow-up, will be presented at the meeting. Conclusions: Early postoperative PET-CT changed the staging and treatment of 14.5% of resected stage III pts, and has the potential for early detection of curable metastatic disease. We currently evaluate this strategy and its actual impact in a prospective trial.

AIM To characterize colorectal cancer (CRC) in octogenarians as compared with younger patients. METHODS A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of 80 years or older between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Fisher’s exact test was used for dichotomous variables and χ2 was used for variables with more than two categories. Overall survival was assessed by Kaplan-Meier survival analysis, with the log-rank test. Cancer specific survival (CSS) and disease-free survival were assessed by the Cox proportional hazards model, with the Fine and Gray correction for non-cancer death as a competing risk. RESULTS The study included 350 patients, 175 patients in each group. Median follow-up was 40.2 mo (range 1.8-97.5). Several significant differences were noted. Octogenarians had a higher proportion of Ashkenazi ethnicity (64.8% vs 47.9%, P < 0.001), a higher rate of personal history of other malignancies (22.4% vs 13.7%, P = 0.035) and lower rates of family history of any cancer (36.6% vs 64.6%, P < 0.001) and family history of CRC (14.4% vs 27.3%, P = 0.006). CRC diagnosis by screening was less frequent in octogenarians (5.7% vs 20%, P < 0.001) and presentation with performance status (PS) of 0-1 was less common in octogenarians (71% vs 93.9%, P < 0.001). Octogenarians were more likely to have tumors located in the right colon (45.7% vs 34.3%, P = 0.029) and had a lower prevalence of well differentiated histology (10.4% vs 19.3%, P = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of PS. Their 5-year CSS was worse (63.4% vs 77.6%, P = 0.009), both for metastatic (21% vs 43%, P = 0.03) and for non-metastatic disease (76% vs 88%, P = 0.028). CONCLUSION Octogenarians presented with several distinct characteristics and had worse outcome. Further research is warranted to better define this growing population.

Background Preoperative chemoradiotherapy is usually not indicated for cT2N0 rectal cancer. Abdominoperineal resection is the standard treatment for distal rectal tumors. The aim of the study was to evaluate the actual sphincter-preservation rate in patients with distal cT2N0 rectal cancer given neoadjuvant chemoradiotherapy. Methods Data were retrospectively collected for all patients who were diagnosed with distal cT2N0 rectal cancer at a tertiary medical center in 2000–2008 and received chemoradiotherapy followed by surgery (5–7 weeks later). Results Thirty-three patients (22 male) of median age 65 years (range, 32–88) were identified. Tumor distance from the anal verge ranged from 0 to 5 cm. R0 resection with sphincter preservation was accomplished in 22 patients (66%), with a 22% pathological complete response rate. Median follow-up time was 62 months (range 7–120). There were no local failures. Crude disease-free and overall survival were 82% and 86%, respectively. Factors associated with sphincter preservation were tumor location (OR = 0.58, p = 0.02, 95% CI = 0.37-0.91) and pathological downstaging (OR = 7.8, p = 0.02, 95% CI = 1.35-45.85). Chemoradiotherapy was well tolerated. Conclusion High rates of sphincter preservation can be achieved after preoperative chemoradiotherapy for distal cT2N0 rectal cancer, with tolerable toxicity, without compromising oncological outcome.

Background To compare the accuracy of different imaging modalities, alone and in combination in predicting findings at surgery after preoperative chemoradiation for locally advanced rectal cancer. Methods Following chemoradiation, tumors were reclassified on the basis of findings on pelvic computed tomography (CT) (94 patients), endorectal ultrasonography (EUS) (138 patients) alone or by both CT and EUS (80 patients). The ability of the imaging modalities, to predict the pathologic T status, N status, and TNM stage at surgery was evaluated and compared. Results Mean age of the patients was 64.5 years (range 28–88 years); 55% were male. CT and EUS combined had a positive predictive value of 20% for pathologic pT1 stage, 29% for pT1, 29% for pT2, and 58% for pT3. Predictive values for the operative TNM stage were 50% for stage I, 45% for stage II, and 31% for stage III. These values did not exceed those for each modality alone. Conclusion The performance of preoperative CT and EUS in predicting the T and TNM stage of rectal cancer at surgery is poor. Neither modality alone nor the two combined is sufficiently accurate to serve as the basis for decisions regarding treatment modification.

Background Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer. Methodology/Principal Findings Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m2 twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%). Conclusions/Significance External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted. Trial Registration ClinicalTrials.gov NCT01784393NCT01784393

There is emerging evidence for the prognostic role of various microRNA (miRNA) molecules in colon cancer. The aim of this study was therefore to compare the miRNA profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995 and 2005 without adjuvant therapy and for whom reliable miRNA expression data were available. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. The results showed that in stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with poor prognosis. In contrast, in stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. In conclusion, this study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer. Based on these results, a validation study is planned.

SUMMARY Earlier reports have described an association between esophageal cancer (EC) and high incidence of other primary tumors (OPTs) of the upper aerodigestive tract and breast cancer. We evaluated the incidence of non-upper aerodigestive OPTs among Israeli EC patients; 2328 EC patients were retrieved from the Israeli National Cancer Registry between 1980 and 2004. The relative risk of OPTs for EC patients was measured using standardized incidence ratio (SIR). Two cohorts, Israeli National Cancer Registry registered colorectal cancer (CRC) patients and the general Israeli population, were used for reference; 297 EC patients (12.7%) had OPTs, including breast (18.9%), CRC (16.2%), prostate (8.8%), and bladder (8.4%) cancers. Upper aerodigestive OPTs were less common. Most OPTs were identified before (74.4%) or simultaneously with (13.8%) EC diagnosis. The median time interval between OPTs diagnoses and EC development was 6.0 years. The incidence of OPTs was significantly higher among EC patients compared with CRC patients (SIR: 2.05, P

To determine whether the use of adjuvant radiation in the treatment of invasive thymic tumors affects survival and to identify prognostic factors.The files of 47 patients with thymic tumors treated by adjuvant radiation in our institute from 1984 to 2003 were reviewed for data on prognosis and survival. All patients underwent thoracotomy followed by either total macroscopic resection (n = 42) or biopsy (n = 5). The radiation dose ranged from 26 to 60 Gy.Median duration of follow-up was 10.6 years. Overall 5-year survival was 73% (60%-88%): 77% for thymoma (n = 35/45) versus 33% for thymic carcinoma (n = 2/6) (P = 0.14). Better survival was associated with lower disease stage (II vs. III/IVA, P = 0.01), resection (P = 0.0004), myasthenia gravis at presentation (P = 0.04), and higher radiation dose (or=45 vs.45 Gy, P = 0.02); sex, smoking, tumor size, pathology, and margin status had no effect. Locoregional relapse occurred in 11 patients and distant metastasis in 4. The 5-year disease-free survival was 67% (52%-86%), with a median time to recurrence of 8.3 years. The better overall survival and disease-free survival associated with higher doses of radiation were also true for stage II patients. On multivariate analyses after adjusting for age, higher disease stage and lower radiation dose were found to adversely affect overall survival and disease-free survival. Thymic carcinoma had an impact only on disease-free survival.Postoperative radiation therapy to doses above 45 Gy may improve the disease-free and overall survival of patients with invasive thymoma, especially stage II. Thymic carcinoma has a worse prognosis.

e14594 Background: The incidence of colorectal cancer (CRC) in young patients (pts) has increased significantly in the last decade. Several studies, including from our group, have evaluated whether CRC in young pts has unique features, with conflicting results. The aim of our study was to compare various characteristics of CRC between young and older pts, while emphasizing potential differences through a younger age cutoff and a larger database. Methods: This was a single center retrospective case control study. We searched our institutional database for all CRC pts 40 years old or younger who were diagnosed between 1997 and 2013. A control group consisted of consecutive pts older than 50 years at CRC diagnosis during the same period. These pts were matched to the study group by their year of diagnosis in a 1:2 ratio. Data on demographics, predisposing risk factors, clinical presentation, disease characteristics, treatment and outcome were compared between groups. Results: A total of 330 pts were included...

e15050 Background: Esophageal cancer (EC) comprises two histopathological subtypes: squamous cell carcinoma (SqCC), usually located in the upper 2/3 of the esophagus, and adenocarcinoma (AdenoCa), ...

To determine pretreatment prognostic variables that predict outcome of radiotherapy for biochemical failure after prostate cancer surgery and evaluate contemporary clinical decision tools for patient selection.Fifty patients were identified with failure after rescue radiation was defined as a confirmed rise in PSA, distant metastases, prostate cancer death, or initiation of hormonal therapy. Univariate analysis and multivariate Cox models were constructed. Outcome was compared with decision tree and recursive partitioning predictive models.The median preradiation PSA (pre-RT PSA) was 1.2 ng/mL and the median dose of radiation was 66.6 Gy; median follow-up was 39.6 months. Overall, the estimated 3-year failure free survival was 54%, 95%CI [43,74]. Seminal vesicle involvement (SVI) (P = 0.003) and preradiation PSA Doubling Time (PSADT)10 months (P = 0.01) were both significant predictors for treatment failure whereas pre-RT PSA was of borderline significance (P = 0.07). On multivariate analysis a pre-RT PSA of1 and SVI were associated with hazard ratios of 6.2 and 7.3 (P = 0.01 and P = 0.004), respectively. An additional Cox model constructed for 31 patients for whom pre-RT PSADT could be calculated showed PSADT and SVI to be independent prognostic parameters. Two predictive models, a decision tree analysis, and a recursive partitioning model were moderately accurate in predicting outcome in this series, however, high-risk patients experienced less treatment failures than predicted.Pre-RT PSA1 ng/mL, longer PSADT (10 months) and no SVI are associated with improved outcome after rescue radiation. Contemporary clinical prediction tools are imperfect predictors of outcome for rescue radiation therapy.

BACKGROUND The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to weight loss, ghrelin and adiponectin levels increase and leptin decreases. Cancer cachexia is a complex metabolic state, characterized by loss of muscle mass and adipose tissue together with anorexia. The authors hypothesized that responses of these hormones may be attenuated in cancer cachexia. METHODS Fasting plasma ghrelin, adiponectin, and leptin levels, as well as weight loss, were determined in 40 cancer patients: 18 of them suffered from cancer-induced cachexia, and 22 served as a comparison group. Hormone levels were measured before administration of cancer therapy. RESULTS A similar distribution of age, gender, and diagnosis was observed in both study groups, but the cachectic patients had higher rates of metastatic disease and lower albumin levels. No significant correlation was observed between plasma adiponectin levels and weight loss. Mean plasma ghrelin levels were higher among cachectic compared with noncachectic patients. Notably, the association between ghrelin levels and weight loss was only modest, and in a third of the cachectic patients, ghrelin levels were equal to or lower than those in the noncachectic group. Plasma leptin levels showed gender-dependent associations, and significantly lower levels were found among cachectic women but not among cachectic men. CONCLUSIONS Results suggested a gender-dependent attenuation of expected physiologic responses to weight loss among cancer cachexia patients. Thus, impaired response of adiponectin, ghrelin, and leptin may play a role in the pathogenesis of cancer cachexia syndrome. Cancer 2006. © 2006 American Cancer Society.

e15078 Background: Many efforts are being made to improve treatment options for advanced esophagogastric cancer (AEGC). The aim of this phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods: Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). To assure regimen's safety a short phase Ib part, with three dose levels, was planned. The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX and to determine the tumor response rate. Results: The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%) and these were usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. Eventually, the recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). The objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. Eighteen patients (82%) derived a clinical benefit: improvement of pain, weight or performance status without a deterioration of any of these factors, from treatment. The median overall survival was 11.3 months (range, 1.5-39.2+ months) and median progression-free survival was 8.7 months (range, 1.3–26.6 months). The 2-year OS rate reached 22.7%. Conclusions: AVDCX was associated with bevacizumab-related fatal toxicities. It seems to reproduce the efficacy of bevacizumab regimen AVAGAST trial, without a clue for significant improvement over common docetaxel regimens in AEGC.

Background Preoperative radiochemotherapy (RCT) is standard in locally advanced rectal cancer (LARC). Initial data suggest that the tumor’s metabolic response, i.e. reduction of its 18 F-FDG uptake compared with the baseline, observed after two weeks of RCT, may correlate with histopathological response. This prospective study evaluated the ability of a very early metabolic response, seen after only one week of RCT, to predict the histopathological response to treatment. Methods Twenty patients with LARC who received standard RCT regimen followed by radical surgery participated in this study. Maximum standardized uptake value (SUV-MAX), measured by PET-CT imaging at baseline and on day 8 of RCT, and the changes in FDG uptake (ΔSUV-MAX), were compared with the histopathological response at surgery. Response was classified by tumor regression grade (TRG) and by achievement of pathological complete response (pCR). Results Absolute SUV-MAX values at both time points did not correlate with histopathological response. However, patients with pCR had a larger drop in SUV-MAX after one week of RCT (median: -35.31% vs −18.42%, p = 0.046). In contrast, TRG did not correlate with ΔSUV-MAX. The changes in FGD-uptake predicted accurately the achievement of pCR: only patients with a decrease of more than 32% in SUV-MAX had pCR while none of those whose tumors did not show any decrease in SUV-MAX had pCR. Conclusions A decrease in ΔSUV-MAX after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned.

e14571 Background: This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiation (CRT) in locally advanced esophageal cancer (LAEC). We hereby report its preliminary results. Methods: Patients (pts) with potentially resectable LAEC, defined as T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A tumors, received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-FU 1000 mg/m2/day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy (RT) given concurrently with 2 cycles of cisplatin 75 mg/m2 and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose of 400 mg/m2, starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: Thirty-six pts have been enrolled to date and 32 completed CRT. The median age was 65 years and 60% were males. The ratio of squamous/adeno histologies was 53%/47%. Pts had very advanced tumors: 95% T3-T4, 63% N1 and 28% M1A. In the absence of dose limiting toxicity, 31 pts received the phase II dose of 5-FU, defined as 1000 mg/m2/day. The most common grade >3 toxicities were leucopenia (51% of pts) and neutropenia (48%). There was one toxic death, due to neutropenic sepsis. Among the 27 operated pts, R0 resection was achieved in 24 (89%). There were 4 cases (15%) of postoperative mortality, due to infection (3 pts) or respiratory failure (1). Downstaging was noted in 83% of pts and pathological complete response (pCR) in 32%. Pts with squamous histology had a higher pCR rate (53% vs 7%, p=0.007). At the time of the analysis, 14 pts (40%) remain free of disease and the local control rate is 92%. Updated results will be presented at the meeting. Conclusions: Preliminary results from this prospective study suggest that the addition of cetuximab to standard CRT is safe. The R0, pCR and local control rates are encouraging. Squamous cell tumors may gain more benefit from the addition of cetuximab.

572 Background: Preoperative radiochemotherapy (RCT) is the standard treatment of locally advanced rectal cancer (LARC), obtaining pathological complete response (pCR) in 15%-30% of cases. Post-RCT reduction of 18F-fluorodeoxyglucose (FDG) uptake within the tumor compared with the baseline, i.e. the tumor's metabolic response, correlates with pCR. However, an earlier prediction of pCR could enable tailored modifications of the treatment. We hence evaluated the correlation between the metabolic response after only one week of RCT for LARC and the actual pCR at the post-RCT surgery. Methods: Patients (pts) were eligible for this prospective study if they had LARC, defined as T3-4NX or TxN+ tumors by pre-treatment PET-CT and endoscopic ultrasound. Pts received standard RCT regimen, consisting of 50.4Gy radiotherapy concurrently with a fluoropyrimidine-based chemotherapy, followed by surgery. Pts underwent baseline FDG-PET-CT imaging within 2 weeks prior to the initiation of RCT and a second one on day 8 of RCT. Maximum standardized uptake value (SUV-max) was measured in both scans and changes in FDG- uptake were recorded. Man-Whitney test was used to evaluate differences in the SUV-max between baseline and day 8 in pts obtaining pCR and those who did not. Results: Twenty pts participated in the study. Half were males and the median age was 64 years. Ten pts had T3N0 tumors and 10 had T3N+ disease. Radical surgery was done in 19 pts and local excision in one. Considering the entire group, there was a borderline-significant difference between the metabolic response of pts with pCR and those without pCR (Chi-square = 3.429, p = 0.064). Yet, the changes in FGD-uptake were able to identify pts who achieved pCR and those who did not: only pts with a decrease of more than 33% in SUV-max had pCR while none of the pts who had less than 8.9% decrease in SUV-max had pCR. Conclusions: A decrease in SUV-max between baseline-PET-CT scans and scans done after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned. No significant financial relationships to disclose.

AIM: To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer. METHODS: The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%). RESULTS: Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups. CONCLUSION: This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.

e14089 Background: Routine PET-CT evaluation is still not indicated for stage III colon cancer (CC). However, accumulating data suggest that it may modify the staging and treatment of these patient...

10635 Background: Preliminary data suggest that microRNAs may have a prognostic role in gastric cancer and may thereby improve our ability to individualize its treatment. We therefore compared the ...

Background: Our ability to determine the prognosis of an individual patient with gastric cancer and thereby to select patients for adjuvant therapy is still limited. Preliminary data suggest that microRNAs may have a prognostic role in this disease. We hence decided to compare the microRNA profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer and to evaluate the prognostic impact of these molecules. Patients and Methods: Eligible patients, who underwent curative gastrectomies between 1995 and 2005 and did not receive any pre- or postoperative adjuvant therapy, were identified from the database of the participating institutions. Total RNA was extracted from tumor formalin-fixed paraffin embedded (FFPE) samples using proprietary protocols that preserve the small RNA fraction. Initial profiling using microRNA microarrays identified potential microRNA biomarkers that can be used to predict recurrence of gastric cancer after resection. The expression of differential microRNAs, was verified by qRT-PCR. Results: Forty-five eligible patients had adequate tumor content and microRNA expression data and were included in the analysis. Of these, 14 (31%) experienced recurrence of disease within three years from surgery (“bad prognosis” group) and 31 (69%) did not (“good prognosis” group). Advanced pathological stage and extensive surgical procedure correlated with bad prognosis. Signal levels of three microRNAs were found to be significantly differentially expressed in tumors from patients with good prognosis vs. patients with bad prognosis. High expression of each of these microRNAs was associated with significantly poorer prognosis for both recurrence and survival. Proprietary microRNA qRT-PCR showed a high correlation to microarrays and similar separation into prognosis groups based on microRNA expression. Conclusion: We identified a set of microRNAs whose high expression was predictive of tumor recurrence and poor prognosis in patients with gastric cancer. This finding provides a basis for a novel tool for risk stratification in this disease and allows further insight into its pathogenesis. Based on these results, a validation study, on a larger and independent cohort of patients, is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3017.