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PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Details of the Patients with HR-DDR Mutations.

Purpose:Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined.Patients and Methods:We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations.Results:The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%.Conclusions:The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.

Veliparib pharmacokinetics compared to historical control.

Written Description of the Supplementary Methods; and the Supplementary Figure/Table Legends

Visual Depiction of the therapy dosing, and pharmacokinetic (PK) sampling schedule for patients in the Phase I portion of the trial.

Veliparib dose levels

Veliparib pharmacokinetics

Perineural invasion is a frequent histological finding in pancreatic adenocarcinoma. However, perineural invasion by intraductal papillary mucinous neoplasm (IPMN), a precursor lesion of pancreatic adenocarcinoma, has not been reported so far. We report a unique case of perineural invasion by IPMN in a 60-year-old female who underwent pancreatoduodenectomy for high-risk features of IPMN. Histological evaluation showed increased nerve density in the connective tissue of IPMN with multiple foci of perineural invasion by IPMN. In addition, there was a discrete 2 mm focus of invasive carcinoma that did not show perineural invasion. Chemotherapy was started and the patient is disease-free at 29 months follow up. The case illustrates previously unreported neuroplastic alterations and neutrotropism in benign neoplastic component of a malignant IPMN.

Background Cancer of unknown primary (CUP) presenting as bone‐predominant (BCUP) or lymph node‐only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the “one‐treatment‐fits‐all” approach. Materials and Methods We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non‐BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan‐Meier method was used to estimate overall survival and compared using log‐rank test. Results In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor‐risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor‐risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil‐to‐lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS. Conclusion BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor‐risk Culine group and high neutrophil‐to‐lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long‐term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site‐directed therapy. Implications for Practice Cancer of unknown primary (CUP) rarely presents as bone‐predominant (BCUP) or lymph node‐only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor‐risk group and neutrophil‐to‐lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided., Considering the limited understanding of bone‐predominant or lymph‐node‐only cancers of unknown primary, this article describes the clinical features and outcome data of these two unique conditions.

Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined. Patients and Methods: We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations. Results: The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%. Conclusions: The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.

Despite aggressive adjuvant management, a high percentage of patients who undergo appropriate surgical resection for pancreatic cancer will see their cancer recur and thus will not be cured. An important paradigm shift to achieve better outcomes has been therapy sequence, with neoadjuvant chemotherapy preceding surgery. Patients with a borderline resectable cancer, or patients with a resectable cancer but who have other high-risk features, are ideal candidates to consider for neoadjuvant chemotherapy. Among the high-risk features, a baseline elevated CA 19-9 concentration can be particularly useful, as its response trend during neoadjuvant chemotherapy can offer important insights into the prognosis after surgery. When selecting a neoadjuvant chemotherapy regimen, response data available for the use of FOLFIRINOX and gemcitabine and nabpaclitaxel in the metastatic setting support their use in this space. FOLFIRINOX is perhaps the preferred regimen, given its proven adjuvant benefit and possibly its superior tumor response rate; still, patient tolerance and thus ability to complete recommended treatment must be carefully considered. This review presents the evidence supporting neoadjuvant chemotherapy for resectable pancreatic cancer, the factors to consider when making such a recommendation, the selection of specific regimens, and our institutional approach using these tools.

PURPOSE: This phase I trial evaluated the maximum tolerated dose, safety and preliminary efficacy of lapatinib, a HER1, HER2 dual kinase inhibitor plus bortezomib, a proteasome inhibitor, in adult patients with advanced malignancies. METHODS: Patients were enrolled in a standard 3+3 design with lapatinib (L) 750, 1000, 1250 or 1500mg daily, and bortezomib (B) 0.7, 1.0, 1.3 or 1.6mg/m(2) 3 weeks on 1 week off. Dose limiting toxicities (DLT) were assessed during the first 28 days. RESULTS: Fifteen patients received the combination of lapatinib and bortezomib in 3 different cohorts and 10 were evaluable for DLT. There were no DLTs. Anorexia was the most common adverse event. Biomarker analysis showed upregulation of p27 expression with lapatinib and the combination. No tumor response was observed and thus the study was closed early. CONCLUSION: The combination of lapatinib and bortezomib was well tolerated but no complete or partial tumor responses were observed at the dose levels tested. ClinicalTrials.gov Identifier .

Multimodality therapy (MMT) is recommended for patients with resectable gastric cancer, but no single approach has been established as standard. Little is presently known about current national practice patterns and sequencing of MMT.Retrospective cohort study of patients with gastric cancer aged 18 to 80 y in the National Cancer Database (2006-2014) with ≥T2 and/or node-positive disease (i.e., stage Ib to III) treated with MMT. Clinical nodal staging accuracy was ascertained among those treated with upfront surgery by comparing clinical and pathologic nodal staging. Multivariable Cox regression was used to evaluate the association between overall risk of death and MMT approach (i.e., radiation used versus not and treatment sequence).Among 5817 patients, 16.1% received perioperative MMT, 50.6% preoperative only, and 33.3% postoperative only. The sensitivity, specificity, positive predictive value, and negative predictive values of clinical nodal staging were 68.4%, 88.8%, 91.1%, and 62.7%, respectively. Current clinical nodal staging modalities understage 37.3% of clinically node-negative patients. Over time, radiation utilization decreased (74.3% in 2006 versus 53.9% in 2014; trend test, P 0.001), perioperative MMT increased (8.9% versus 22.2%%; trend test, P 0.001), and postoperative MMT decreased (43.1% versus 21.0%; trend test, P 0.001). Neither type of MMT nor treatment sequence is associated with risk of death.One-third of patients with gastric cancer who are candidates to receive MMT are treated with upfront surgery. Given the high false negative rate of clinical nodal staging and high noncompletion rate of postoperative treatment, efforts should be directed at improving and optimizing preoperative therapy utilization.

Medical therapy plays a vital role in the neoadjuvant, adjuvant, and palliative management of patients with pancreatic cancer. The medical therapeutic options are largely limited to chemotherapy, and thus consideration for toxicity to balance with intended anticancer effect is requisite. The possible goals of therapy therefore need clear establishment at the outset. Various imaging modalities are an important part of the toolset needed to ascertain the baseline status of a cancer in terms of potential for resection, which will ultimately guide the treatments recommended and sequences of their use. These same imaging modalities remain critical to the assessment of treatment response over time. A considered understanding on how to use these imaging tools is important to ensure that a thorough and focused assessment of a patient’s cancer is achieved, and to tailor management to the individualized goals of the patient. In this chapter, the role of various imaging modalities will be discussed in the context of oncologic management.

Purpose: Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors. Experimental Design: We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012–2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302). Results: Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68–0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts. Conclusions: Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.

The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population. CLINICALTRIALS.NCT02353026.

PURPOSE/OBJECTIVE(S) The role of RT remains controversial in treating BRPC and LAPC following Alliance A021501 and LAP07. These studies shifted our institutional practice to more selective use of RT, whereas in the past, we most often consolidated with RT after chemotherapy (chemo). We reviewed our experience using modern multi-agent chemo with or without RT. MATERIALS/METHODS We utilized a retrospective registry to analyze 454 pts (240 M, 214 F, median age 65 [28 - 89]) who were diagnosed with BRPC (n = 172) or LAPC (n = 282) between 2011 to 2019 and who underwent chemo alone (n = 167) or chemo then RT (n = 287). For those pts who received RT, the median dose and fractionation was 50 Gy (30 - 98 Gy) and 15 fractions (4 - 28). Median biological effective dose was 60 Gy (33 - 132 Gy). All pts received FOLFIRINOX (n = 274) or gemcitabine/nab-paclitaxel (GnP, n = 180). Associations between chemo regimen (FOLFIRINOX vs. GnP), resection (surgery vs. no surgery), CA19-9 response (normalized vs. not vs. not applicable [N/A]), and other demographic characteristics were tested using the likelihood-ratio. CA19-9 normalizers were defined by the minimum CA19-9 value between the start of chemo and 6 mos post-chemo start that was < 40 U/mL. Pts were classified as N/A if the pt either had an abnormal bilirubin level or a CA19-9 < 40 U/mL at baseline, or were missing CA19-9 data. Kaplan-Meier and Cox proportional hazards tests were used for survival analyses. RESULTS For all pts, median overall survival (OS) was 17.5 mos and median distant metastasis free survival (DMFS) was 11.5 mos. The chemo then RT group had a greater proportion of pts who received FOLFIRINOX than the chemo only group (64% vs 54%, P = 0.03). The chemo then RT group also had a greater percentage of pts who went to surgery than the chemo alone group (33% vs 16%, P < 0.0001). Pts with BRPC were more likely to receive surgery than pts with LAPC (48% vs. 14%, P < 0.0001). Univariate analyses showed that baseline stage (BRPC vs LAPC), surgery, CA19-9 response, and receipt of chemo then RT were associated with both OS and DMFS. Chemo regimen was associated with OS but not DMFS on univariate analysis. Multivariate analysis identified that surgery, CA19-9 response, and receipt of chemo then RT were independent prognostic factors for both OS and DMFS (Table). Multivariate analysis of only LAPC showed the same associations with OS and DMFS as with all pts. CONCLUSION RT following chemo was associated with better OS and DMFS compared with chemo alone in a modern retrospective BRPC and LAPC cohort. Additional studies are needed to clarify the role of RT.

Resection techniques for esophageal carcinoma continue to evolve, from endoscopic mucosal resection or endoscopic submucosal dissection for early stage disease to standard and robot-assisted minimally invasive esophagectomy as part of multimodal therapy for locally advanced disease. Though currently limited to assessing conduit perfusion and sentinel lymph nodes, embedded technology in the robotic surgical platform will likely play an expanded role during esophagectomy in the future. The use of targeted therapies, checkpoint inhibitors, engineered immune cell therapy, and cancer vaccines show promise in the treatment of systemic disease. Radiation therapy techniques are becoming increasingly sophisticated and they may play a more active role in stage IV disease in the future.

4622 Background: Immunotherapy is emerging as a potent therapy for a range of hematologic malignancies and solid tumors. To target pancreatic carcinoma we have developed an autologous, non-engineered T cell therapy using T cell lines that simultaneously target the tumor-associated antigens (TAAs) PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin. These multiTAA-specific T-cell lines could be consistently prepared by culturing PBMCs in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail, and adding autologous pepmix-loaded DCs as APCs. Methods: Patients with locally advanced or metastatic pancreatic adenocarcinoma who achieved cancer control with three months of standard chemotherapy were eligible to receive up to 6 infusions of multiTAA T-cells (fixed dose - 1x107 cells/m2). While also continuing the same chemotherapy, T-cells were given at monthly intervals from month four, onwards. The primary study endpoints were safety and feasibility of completing all 6 planned infusions, with secondary and tertiary endpoints including anti-tumor effects, patient survival, in vivo expansion and T cell persistence of the infused cells as well as recruitment of the endogenous immune system. Results: Between June 2018 and December 2019, we treated 13 patients with multiTAA T-cells. For 12/13 patients, we generated sufficient cells for all 6 planned doses; 2 doses were available for the remaining patient. Of the 13 patients, 8 maintained cancer control for a longer than expected duration, compared to historical controls. With administration of T-cells, 3 of these 8 patients had partial responses and 1 patient had a radiographic complete response (per RECIST). These responses were seen in patients with metastatic cancer. Notably, no patient had infusion-related systemic- or neuro-toxicity. Thus, infusion of autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin has been safe and provided durable clinical benefit to patients with pancreatic adenocarcinoma. Conclusions: Autologous, TAA cytotoxic T-cells can reliably be generated and safely administered to patients in conjunction with standard of care chemotherapy. In some patients, addition of T-cells may extend duration of first line therapy cancer control and induce additional tumor responses, and activation of the endogenous immune system has been documented in all patients. Exploration in a higher phase study is warranted. Clinical trial information: NCT03192462 .

Purpose To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC). Methods This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1–7 and 150 mg/m2 TMZ PO daily on days 1–5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03. Results We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months. Conclusion The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit. ClinicalTrials.gov Identifier NCT01205828. Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2852-2) contains supplementary material, which is available to authorized users.

// Brandon G. Smaglo 1 , Anteneh Tesfaye 2 , Thorvardur R. Halfdanarson 3 , Joshua E. Meyer 4 , Jue Wang 5 , Zoran Gatalica 6 , Sandeep Reddy 6 , David Arguello 6 and Patrick M. Boland 7 1 The Ruesch Center for the Cure of GI Cancers, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA 2 Departments of Hematology/Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA 3 Department of Medicine, Mayo Clinic, Rochester, MN, USA 4 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA 5 Division of Oncology, University of Arizona Cancer Center, Phoenix, AZ, USA 6 Department of Pathology, Caris Life Sciences, Phoenix, AZ, USA 7 Department of Medicine, GI Center, Roswell Park Cancer Institute, Buffalo, NY, USA Correspondence to: Brandon G. Smaglo, email: // Keywords : anal squamous cell carcinoma, biomarker analysis, tumor profile Received : May 15, 2015 Accepted : October 09, 2015 Published : October 20, 2015 Abstract Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with in situ hybridization. Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well.

Biotherapeutics are attractive anti-cancer agents due to their high specificity and limited toxicity compared to conventional small molecules. Antibodies are widely used in cancer therapy, either directly or conjugated to a cytotoxic payload. Peptide therapies, though not as prevalent, have been utilized in hormonal therapy and imaging. The limitations associated with unmodified forms of both types of biotherapeutics have led to the design and development of novel structures, which incorporate key features and structures that have improved the molecules' abilities to bind to tumor targets, avoid degradation, and exhibit favorable pharmacokinetics. In this review, we highlight the current status of monoclonal antibodies and peptides, and provide a perspective on the future of biotherapeutics using novel constructs.

BACKGROUND For locally advanced rectal cancer, response to neoadjuvant radiation has been associated with improved outcomes but has not been well characterized in general practice. The goals of this study were to describe disease response rates after neoadjuvant treatment and to evaluate the association between disease response and survival. MATERIALS AND METHODS Retrospective cohort study of patients aged 18-80 y with clinical stage II and III rectal adenocarcinoma in the National Cancer Database (2006-2012). All patients underwent radical resection after neoadjuvant treatment. Treatment responses were defined as follows: no tumor response; intermediate-T and/or N downstaging with residual disease; and complete-ypT0N0. Multivariable, multinomial regression was used to evaluate the association between neoadjuvant radiation use and disease response. Multivariable Cox regression was used to evaluate the association between disease response and overall risk of death. RESULTS Among 12,024 patients, 12% had a complete and 30% an intermediate response. Neoadjuvant chemotherapy alone was less likely to achieve an intermediate (relative risk ratio: 0.70 [0.56-0.88]) or a complete response (relative risk ratio: 0.59 [0.41-0.84]) relative to neoadjuvant radiation. Tumor response was associated with improved 5-y overall survival (complete = 90.2%, intermediate = 82.0%, no response = 70.5%; log-rank, P

716 Background: Pancreatic ductal adenocarcinoma (PDAC) has been highly resistant to immunotherapeutics to date. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC are treated with LOAd703 intratumoral injections and standard nab-paclitaxel/gemcitabine (nab-P/G) chemotherapy. Starting on cycle 1 day 15 of nab-P/G, LOAd703 is injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects are eligible to receive 6 more injections. Three dose levels of LOAd703 are being investigated using a BOIN dose escalation design. Primary endpoints are safety and feasibility. Secondary endpoints include response rate and overall survival. Results: To date, 13 subjects are evaluable for safety and feasibility. Three patients were treated at dose 1 (5x10e10 VP), 4 subjects at dose 2 (1x10e11 VP), and 6 subjects at dose 3 (5x10e11 VP). The most common adverse events (AEs) attributed to LOAd703 have been fever, chills, nausea, and increased transaminases. AEs have been transient and grade 1-2, with the exception of a grade 3 transaminase elevation in 1 subject receiving dose 3 (the only dose-limiting toxicity observed thus far). During protocol treatment, circulating MDSCs decreased in 8/13 subjects while effector memory T-cells increased in 10/13. ELISPOT analyses showed a rise in tumor antigen-specific T-cells in 10/13 subjects. At the lowest dose level, best response was stable disease, and 6/10 patients who received higher LOAd703 doses have had partial responses. Only 1 patient has had progressive disease as best response. Conclusions: Adding LOAd703 to nab-P/G has been safe and feasible. Treatment-emergent immune responses have been demonstrated in most subjects, with a notable proportion having objective anti-tumor responses. Clinical trial information: NCT02705196.

4015 Background: 17 – 25% of mPDACs harbor DNA damage response (DDR) mutations, the presence of which can be predictive of a response to platinum and PARP inhibitor-based therapy. The PARP inhibitor, Vel is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. Methods: We initiated a Phase I/II trial of Vel + FOLFOX in pts with mPDAC. Pts received standard mFOLFOX6 except without the 5FU bolus, Q2 weeks. For the Phase I portion, a 3+3 dose escalation of Vel identified a recommended Phase II dose of 200mg orally BID, days 1-7, Q2 weeks. For the Phase II portion, we enrolled two cohorts: 1) Untreated pts; 2) Previously treated pts. Also, for Phase II, pts were pre-selected if they had either a pathogenic germline or somatic DDR mutation (e.g. BRCA1/2, PALB2, ATM), and/or a family history suggestive of a breast or ovarian cancer syndrome (labelled FH+). Objective response rate (ORR) was the primary objective of the Phase II cohorts; key secondary endpoints were median progression-free survival (PFS) and overall survival (OS). Results: Between 01-2011 and 12-2018, 64 pts received treatment, 31 in Phase I, and 15 untreated and 18 previously treated in Phase II. The combination was well tolerated, with the main Grade 3/4 AEs being myelosuppression (16%) and nausea/vomiting (6%). Of the 64 pts, 55% were male; median age was 64; 95% had an ECOG PS of 1; 78% were platinum-naïve; 69% were FH+; and 27% had a known DDR mutation. 57 pts were evaluable for response, and the ORR, PFS, and OS for the different pt subgroups are detailed below. The Phase II cohorts achieved the primary endpoint of an ORR ≥ 25%. Most notably, plat-naïve, FH+, and DDR mutation+ pts had an ORR of 58%. Conclusions: The combination of Vel + FOLFOX is safe, well tolerated, and shows promising efficacy particularly in plat-naïve pts who are FH+ and/or harbor DDR mutations. A randomized trial to assess the contribution of Vel to the regimen is warranted. Clinical trial information: NCT01489865. [Table: see text]

To determine the association between neoadjuvant chemotherapy and chemoradiation therapy on completeness of pathologic response and to assess the impact of primary tumor versus nodal response on survival after esophagectomy.Patients aged 18 to 80 years in the National Cancer Data Base (2006-2016) with clinically staged, locally advanced (cT2-4 or cN+) esophageal adenocarcinoma who underwent an R0 esophagectomy after neoadjuvant chemotherapy or chemoradiation therapy were included. Multivariable Cox proportional hazards regression models were constructed to assess the association between treatment response and survival.Among 2870 patients, there was a significant dose-response association between completeness of response and overall survival: no response (reference), partial response (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.72-0.91), and complete response (HR, 0.55; 95% CI, 0.47-0.65). Compared with neoadjuvant chemotherapy alone, neoadjuvant chemoradiation was associated with higher pathologic primary tumor (33.9% vs 21.3%; P .001) and pathologic nodal response rates (55.9% vs 32.7%; P .001). Both a primary and nodal response were associated with improved survival. However, among patients with a primary but no nodal response, primary tumor response was not associated with risk of death (HR, 0.88; 95% CI, 0.69-1.11). In contrast, among patients who had a nodal but no primary response, the survival benefit of a nodal response was maintained (HR, 0.66; 95% CI, 0.58-0.76).Pathologic nodal (rather than primary tumor) response to neoadjuvant therapy is associated with improved survival. These data suggest a need to optimize neoadjuvant strategies associated with more complete nodal response rates and to consider more aggressive adjuvant treatment for patients with residual nodal disease after esophagectomy.

The optimal adjuvant management of patients with resectable gastric cancer remains a therapeutic challenge. Although the benefit of adjuvant therapy for these patients is clearly established, recurrence and mortality rates remain high despite such treatment. Moreover, surgical comorbidities and treatment toxicities result in high rates of failure to complete treatment after surgery. Two divergent approaches to adjuvant treatment have emerged as standard: postoperative chemoradiotherapy and perioperative chemotherapy. Because these approaches have never been compared directly, recommendations for adjuvant treatment require multidisciplinary discussion. During this discussion, the characteristics of the symptoms, the histology, location, and stage of the tumor, and the feasibility of the patient's completing all recommended therapy may be considered. In our own practice, we favor perioperative chemotherapy for patients with asymptomatic, proximal, higher-stage disease and adjuvant chemoradiotherapy for patients with symptomatic, distal, lower-stage disease. Herein, we summarize the available data for approaches to the adjuvant treatment of gastric cancer, with special consideration of the characteristics of the patients enrolled in the various studies. We also describe how we developed our paradigm for recommending a particular approach to adjuvant treatment for each patient.

The curative surgical resection of metastatic disease in patients with stage IV colorectal cancer with a limited tumor burden is standard of care. However, the role for neoadjuvant medical therapy and the ideal composition of that therapy are not established. Several neoadjuvant medical therapies, including standard advanced colorectal cancer chemotherapy regimens-such as folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX); folinic acid, 5-FU, and irinotecan (FOLFIRI); and folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI)-have been evaluated, as has the addition of the biologic agents bevacizumab, panitumumab, and cetuximab. Those patients who are immediate surgical candidates do not seem to benefit from a neoadjuvant medical approach and should proceed directly to surgical resection. Those patients who are not surgical candidates at presentation can in some instances achieve a conversion of disease to a curable state with systemic therapy. Here, we review the studies that have explored different treatment regimens, therapeutic sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We also describe how we have established our own treatment paradigm for the management of potentially curable metastatic colorectal cancer.

Gastroesophageal adenocarcinomas represent one of the top five most common types of cancer worldwide. Despite significant advancement, it is still not known which first-line chemotherapy option is best matched to an individual patient. The vast advances in molecular biology have led to the discovery of many potential predictive biomarkers, such as HER-2 neu, thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and topoisomerase-1 (TOPO1). These markers could allow us to select treatment based on an individual’s tumor profile, resulting in an improvement of outcome. Our report highlights two patients with metastatic gastric cancer that achieved an exceptional response with traditional therapy and provides insights into the future perspectives of molecular profile-directed chemotherapy.

e15039 Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) (Mayer et al. NEJM 2015;372:1909-19). An expanded-access program (EAP) for patients with refractory mCRC assessed FTD/TPI safety in a real-world setting. One limitation of RECOURSE was the small number of African-American (AA) patients enrolled in the study (n=8). The EAP enrolled 45 AA patients, enabling assessment of FTD/TPI safety in this population. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy and an ECOG performance status of 0 or 1 were enrolled in this open-label EAP. Patients received FTD/TPI 35 mg/m2 twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. We investigated duration of exposure to FTD/TPI and associated adverse events (AEs) in AA patients to compare them with non-AA and US patients from RECOURSE. Results: Median duration of FTD/TPI therapy for AA patients in the EAP was 9.7 weeks, similar to non-AA patients in the EAP (9.7 weeks) and US patients in RECOURSE (8.9 weeks) (differences not statistically significant). 73.3% of AA patients (n=33) in the EAP discontinued treatment due to disease progression and 8.9% (n=4) discontinued due to AEs. AEs related to FTD/TPI are summarized in the table. Conclusions: Lung cancer patients in Eastern North Carolina possess a strikingly poor inflammatory signature with significant implications for quality of life and survival. Clinical trial information: NCT02286492. [Table: see text]

Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three separate components: an antibody that binds to a cancer cell antigen with high specificity, an effector molecule that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not separate from the antibody during transit and will reliably release the effector to the cancer cell or tumour stroma. The high affinity antibody-antigen interaction allows specific and selective delivery of a range of effectors, including pharmacologic agents, radioisotopes, and toxins, to cancer cells. Some anticancer molecules are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.

Inhibition of tumor angiogenesis has emerged as an important therapeutic component in the management of metastatic colorectal cancer. Three anti-angiogenic agents are currently approved in this clinical setting: bevacizumab, ziv-aflibercept, and regorafenib. Bevacizumab, a monoclonal antibody that targets the angiogenesis-driving ligand vascular endothelial growth factor A (VEGF-A), is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer, where it can be used in combination with intravenous 5-fluorouracil-containing chemotherapy regimens. In conjunction with second-line chemotherapies, bevacizumab also has anti-cancer activity, both for the management of metastatic colorectal cancer in patients who received it as a part of their first line therapy and for those who are naïve to it. Ziv-aflibercept also has demonstrated clinical activity in conjunction with the chemotherapeutic regimen FOLFIRI in the second line management of patients with metastatic colorectal cancer; it functions by binding VEGF-A to the vascular endothelial growth factor proteins VEGF-B and PIGF (placental growth factor). Regorafenib, which inhibits multiple tyrosine kinases, including the VEGF receptors, has proven clinical benefit in the management of patients with metastatic colorectal cancer refractory to all other therapies. For patients’ whose cancers are refractory to all other therapies, there is also evidence for the use of bevacizumab with fluoropyrimidine monotherapy, but only in the bevacizumab-naïve patient subset. Presently, it is not clear if any one agent as more activity in a particular line of therapy than another, has greater efficacy when paired with a particular chemotherapy backbone, or if a particular patient subset is more likely to benefit from these agents. Given the present benefit and tolerance data, an anti-angiogenic agent should be considered in all lines of therapy in the management of metastatic colorectal cancer, with the evidence for the use of these agents in each specific line of therapy and in specific chemotherapeutic combinations driving agent selection.

148 Background: Althoughmultimodality therapy (MMT) is recommended for most patients with resectable gastric cancer, no single approach has been established as standard. As such, little is known about current national practice patterns and MMT treatment sequencing for patients with gastric cancer. Methods: This was a retrospective cohort study of ≥ T2 and/or node positive gastric cancer patients treated with MMT using the National Cancer Database (2006-2012). Patients were categorized based on type of MMT (chemotherapy, concurrent chemoradiation (cXRT), or both chemotherapy and cXRT) and treatment sequence (preoperative, postoperative, or perioperative). Accuracy of pre-treatment clinical nodal staging was ascertained by comparison to pathologic nodal staging in patients treated with upfront surgery. Multivariable Cox regression was used to evaluate the association between overall risk of death and MMT type and sequence. Results: Among 4,857 patients, 14.1% were treated perioperatively, 48.0% preoperatively, and 37.9% postoperatively. Rates of chemotherapy, cXRT, and both chemotherapy and cXRT were 32.1%, 53.4%, and 14.5%. Among patients treated with upfront surgery, sensitivity, specificity, PPV, and NPV of clinical nodal staging were 70.7%, 88.8%, 92.1%, and 62.2%, respectively. Over the study period, use of cXRT decreased (61.8% 2006 vs 52.0% 2012; trend test, p < 0.001) while use of chemotherapy increased (23.6% vs 35.7%; trend test, p < 0.001) and use of both chemotherapy and cXRT did not change. There was an increase in the use of perioperative treatment (8.1% vs 17.4%; trend test, p < 0.001) while postoperative treatment decreased (44.4% vs 31.1%; trend test, p < 0.001). After multivariable modeling, neither type of MMT nor treatment sequence was associated with risk of death. Conclusions: Although current national practice patterns favor pre- and perioperative treatment, one third of patients were treated with upfront surgery. Survival was not associated with MMT type or sequence. However, given the high false negative rate of clinical nodal staging and high non-completion rate of postoperative treatment (50% in MAGIC trial), efforts to improve gastric cancer outcomes should focus on increasing use of preoperative therapy.

TPS507 Background: No effective therapy is available for patients (pts) with advanced cholangiocarcinoma (CC) after disease progression on first-line chemotherapy. In Phase I studies, pembrolizumab (pem) showed activity in pts with advanced CC. Interferon alpha-2b was shown to increase tumor immune infiltrates. In order to improve the response rate (RR) of pts with CC to pem, we propose to combine sylatron with pem in an open-label, single-arm, multicenter Phase II study. Methods: To be eligible for study, pts must have CC, manifesting as either intrahepatic, extrahepatic or gallbladder cancer that is unresectable, metastatic, and has either failed to respond to or demonstrated progression on frontline chemotherapy. Forty-four pts will be enrolled on study to receive SC sylatron (200 mg) weekly for 12 weeks, and IV pem (200mg) once every 3 weeks, starting on week 4 (at the same time as the 4th dose of sylatron), until pts experience disease progression or unacceptable toxicity, or withdraw consent. CT scans will be performed every 9 weeks. The primary endpoints are overall RR (ORR) and the safety and tolerability of combined pem and sylatron therapy. Secondary endpoints include OS, PFS, and ORR by irRECIST. An initial 3-week window will exist in which to evaluate the effect of sylatron alone (following prior chemotherapy) on the tumor microenvironment: one biopsy (biopsy 1) will be obtained before the start of sylatron therapy, and another (biopsy 2) after the third but before the fourth injection of sylatron (and the initiation of pem plus sylatron combination therapy). The effect of sylatron on the CC immune microenvironment will be studied by comparing biopsies 1 and 2. Immune microenvironment in pem + sylatron responders will be compared with non-responders. The study will assess whether the addition of sylatron improves the RR of pem from 17% to 35% in pts with advanced CC. Simon’s two-stage optimum design will be used to test the null hypothesis that P ≤ 0.17 vs. the alternative hypothesis that P ≥ 0.350. This study design provides 80% power (one-sided significance level of 0.05). The time-to-event endpoints (PFS, OS) will be estimated using Kaplan-Meier methodology.

107 Background: Recent data from the MAGIC trial show that pathologically positive lymph nodes (ypN+) despite neoadjuvant (NA) chemotherapy are associated with poorer survival. Although the use of NA therapy has increased, pathologic disease response to multimodality therapy (MMT) and its impact on outcome have not been well-defined. Methods: This retrospective cohort study of the National Cancer Database included patients with cN+ gastric cancer who underwent NA therapy followed by surgical resection between 2006 and 2012. Patients were categorized by NA treatment (chemotherapy or concurrent chemoradiation). Pre-treatment clinical (cN) and pathologic nodal staging (ypN) were used to determine downstaging rates from cN+ to ypN0. The association between overall risk of death and NA treatment, nodal response, and the use of adjuvant therapy was evaluated with multivariable Cox regression. Results: Among 1,489 patients with cN+ gastric cancer receiving NA therapy, 45.5% were treated with chemotherapy and 54.5% with chemoradiation. Rates of nodal downstaging were 29.9% for chemotherapy and 45.4% for chemoradiation. On multivariable analysis, treatment sequence and type were not associated with risk of death. Median survival was significantly lower in patients with ypN+ compared to those with ypN0 disease (27.7 vs 79.7 months; log-rank, p < 0.001).Among patients with ypN+ disease (n = 918), median survival was greater if adjuvant therapy was received (32.6 months vs. 25.3 months, log-rank, p < 0.001); adjuvant therapy was associated with a 19% decreased risk of death (Hazard Ratio [HR] 0.81; 95% CI 0.66-0.99), with further reduction among those who underwent a margin negative resection (HR 0.73; 95% CI 0.58-0.92). In patients with ypN0, adjuvant therapy was not associated with a lower risk of death. Conclusions: Over one third of node-positive gastric cancers demonstrated pathologic nodal downstaging with NA treatment, with chemoradiation yielding a higher response than chemotherapy. Patients with ypN+ had worse survival, and appeared to benefit from adjuvant therapy. Future gastric cancer trials should better define the role for NA chemoradiation and help individualize the use of adjuvant therapy based on nodal response.

e15670Background: The role of radiotherapy in the management of inoperable pancreatic cancer continues to be nebulous. SBRT has emerged as an attractive treatment option due to its short treatment ...

4035Background: Patients (pts) with esophageal cancer (EsophCa) have a poor prognosis and limited treatment options. The effect of histological subtype on tumor molecular profile remains unknown. H...

TPS3624Background: Maintenance therapy with a fluoropyrimidine plus bevacizumab is a widely accepted strategy in the treatment of mCRC, having been shown significant improvement in progression-free...

2589Background: We demonstrated in mouse xenografts that CDK4/6 inhibition with palbociclib (P) is synergistic with 5FU in suppressing tumor growth. Based on these preclinical data, we initiated a Phase I trial to evaluate the safety and activity of P plus 5FU. Methods: Eligible patients (pts) had advanced, retinoblastoma (Rb)-positive (as demonstrated by IHC) solid tumors with an adequate performance status and intact organ function. The first stage of the study was a dose escalation to identify the recommended phase II dose (RP2D) of P in this combination (n = 21). The second stage is an ongoing schedule optimization, in which the timing of the P and 5FU are varied to identify the most effective sequence, as demonstrated by Ki67 suppression (n = 8 to date). All pts underwent tumor biopsies prior to treatment (tx), after 7 days of P, and again after the 5FU infusion. Results: Six pts were enrolled at a P dose of 50mg orally daily, Days 1-7, and IV 5FU as a 400mg/m2 bolus Day 8, and 2400mg/m2 continuous i...

Chemotherapy is proven to play a central role in the adjuvant management of pancreatic cancer. A number of studies have validated its small but significant survival benefit to patients following surgical resection, but many questions about the optimal adjuvant chemotherapeutic management of pancreatic cancer still persist. Currently, the benefits of both the chemotherapeutic agents gemcitabine and 5-fluorouracil have been validated as adjuvant options, with a preference for gemcitabine emerging based on its greater tolerability. Methods to individualize the selection of an adjuvant agent based on an individual tumor's characteristics are being explored, and additional novel agents and regimens are actively being investigated. In the studies that established chemotherapy's adjuvant benefit, a controversy simultaneously developed as to the role of the concurrent use of adjuvant radiation therapy in addition to chemotherapy, leading to the development of a conflicting consensus on how to adjuvantly manage pancreatic cancer patients. Chemotherapy given concurrently with radiation therapy has emerged as the preferred adjuvant approach in the United States, whereas chemotherapy alone is preferred in Europe. In addition to the debate over modality, a separate debate of treatment timing has emerged from studies of neoadjuvant therapy, which has demonstrated a survival benefit in the management of pancreatic cancer, but has not been directly compared with postsurgical adjuvant therapy. This review discusses the evidence for chemotherapy in the adjuvant management of pancreatic cancer, including both the choice of agent and value of concurrent radiation therapy, as well as future directions with novel agents and regimens, techniques of response prediction, and timing to postsurgical adjuvant versus neoadjuvant therapy.

461 Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related death worldwide. Most HCCs develop in severely damaged liver. Methods: The effect of multiple treatment options on liver function (LF) and disease outcome of patients (pts) with HCC (n = 185) were examined retrospectively. Pt tumor burden (using Barcelona clinic liver cancer [BCLC] classification) and LF (Child Pugh [CP]) were assessed at time of diagnosis and then after treatment. Using Kaplan Meier with log rank and T tests, BCLC and CP scores were correlated with overall survival (OS) following individual treatment regimens. Results: We show that better BCLC and LF scores at time of diagnosis predict a better outcome (median OS; p < 0.05). Pts received one or more of the following: no treatment, experimental treatment, TACE, Y90 radioembolization, radiofrequency ablation, resection, radiation, and sorafenib (SFB). Considering all treatment scenarios, LF improved in 9.5%, did not change in 33%, and worsened in 57% of pts. Sixty percent of untreated pts experienced LF decline, compared with 33, 54, 48 and 50% of pts receiving TACE, SFB, TACE/SFB, and Y90/SFB, respectively (no significant differences [NS]); 72% of pts receiving TACE/Y90/SFB (NS); and 85% of pts receiving other Y90/SFB combinations (p = 0.006). In general, pts who saw no change or an improvement in LF from baseline had longer median OS versus pts who had declining LF (p < 0.002). However, pts receiving TACE/Y90/SFB (n = 29) had similar OS to those receiving TACE/SFB (n = 35), despite the toxicity difference (72% [TACE/Y90/SFB] vs. 48% [TACE/SFB] of pts had declining LF). TACE/SFB or TACE/Y90/SFB led to longer median OS than any other treatment group (p = 0.017). Conclusions: The outcome of pts with HCC depends on disease stage and LF. Most pts experience LF decline during treatment. Despite LF decline in 48% of pts receiving a SFB/TACE, these pts experienced longer median OS than pts on any other treatment. Balancing survival benefit with liver toxicities is critical to the successful treatment of pts with advanced HCC. Agents with good antitumor activity and minimal liver toxicity are desperately needed for these pts.

444 Background: Stereotactic body radiation therapy (SBRT) is a novel treatment modality for unresectable, locally advanced pancreatic cancer (LAPC). SBRT delivers high doses of radiation over a shorter duration, with minimal acute toxicities, compared with conventional radiation therapy (CRT) using intensity modulated radiation therapy (IMRT) or 3D conformal techniques (3D-CRT). Few studies have compared outcomes between SBRT and CRT techniques. We conducted a retrospective matched pair analysis of LAPC patients receiving chemotherapy and either SBRT or CRT to assess local control (LC), progression-free survival (PFS), and overall survival (OS). Methods: We retrospectively analyzed 28 patients with LAPC who were treated between August 2006 and August 2014 with 5-FU- or gemcitabine-based chemotherapy combined with CRT (45–56 Gy over 25–28 fractions) or SBRT (25–30 Gy over 5 fractions). Fourteen patients treated with CRT were matched with 14 patients treated with SBRT for age (< 65 vs. ≥ 65 years); nodal staging (N0 or N1); and chemotherapy type (gemcitabine-based or 5-FU-based, administered either concurrently or as induction therapy). Tumor response was assessed using RECIST and all outcomes were calculated from the date of diagnosis. The Log Rank test of Kaplan-Meier curves was used for statistical analyses. Results: Median follow-up time was 11 months (mo). The median duration of LC, PFS, and OS for the entire cohort was 11, 8, and 14 mo, respectively. Median duration of LC was 10 mo for CRT and 11 mo for SBRT (p > 0.05). Median PFS was 8 mo for both groups (p > 0.05). The median OS times were 12 mo for SBRT and 16 mo for 3D-CRT/IMRT (p > 0.05). Conclusions: In this small matched-pair analysis, LAPC patients treated with chemotherapy had similar outcomes following 5 fractions of SBRT as compared with a protracted course of CRT. Given the shorter treatment duration with SBRT, further study is warranted with increased cohort sizes and stratification by other patient and disease characteristics.