bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience.
Authors: Ohba Akihiro , Ueno Hideki , Sakamoto Yasunari , Kondo Shunsuke , Morizane Chigusa , Okusaka Takuji
Published: January 2019

469

Background: Various modified FOLFIRINOX (mFFX) regimens have been reported and widely used in clinical practice. Although there are retrospective studies and single-arm phase 2 studies comparing modified regimens to the full-dose regimen of the historical control group, head-to-head comparisons in the same population are limited. This study aimed to compare mFFX with full-dose FOLFIRINOX (fFFX) in patients with advanced pancreatic cancer (APC). Methods: We reviewed 85 patients with APC who received mFFX (no bolus fluorouracil and irinotecan 150 mg per square) or fFFX as first-line chemotherapy between January 2014 and December 2016. mFFX has been used since January 2016 on the basis of results of a Japanese phase 2 study. The efficacy, safety, and dose reduction pattern were evaluated. Results: A total of 56 eligible patients (26 treated with mFFX and 30 with fFFX) were selected. Baseline characteristics of each group were well-balanced. The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. Second cycle dose reduction occurred in 38% of the patients in the mFFX group and in 62% of those in the fFFX group. The median overall survival (OS) was 19.0 months in the mFFX group, compared to 13.2 months in the fFFX group (HR 0.60, 95% CI 0.25–1.47, P = 0.27). In a multivariate analysis to adjust for prognostic factors for OS, the hazard ratio for death with mFFX was significant (adjusted HR 0.36, 95% CI 0.14–0.93, P = 0.04). The median progression-free survival was 8.3 months in the mFFX group and 5.9 months in the fFFX group (HR 0.83, 95% CI 0.44–1.54, P = 0.55). The response rate was 35% in the mFFX group versus 30% (P = 0.78) in the fFFX group, respectively. Grade 3 or 4 leucopenia (15% versus 40%), neutropenia (42% versus 70%), febrile neutropenia (8% versus 17%), and nausea (4% versus 13%) were decreased in the mFFX group, but the differences were not statistically significant. Conclusions: mFFX had equivalent or higher efficacy and improved safety compared to fFFX in the same population.
The association of an exosomal form of PD-L1 with immunosuppressive activity and gastric cancer prognosis.
Authors: Fan Yibo , Che Xiaofang , Li Zhi , Qu Xiujuan , Liu Yunpeng
Published: January 2019

47

Background: The greatest challenge in cancer immunotherapy is to identify efficient predictive biomarkers to select patients for treatment. Though tumor cell membrane PD-L1 has been most anticipated, tumor cell membrane PD-L1 does not correlate with higher response rates and predict for clinical benefit. Subsequently studies showed that the prognostic value of tumor cell membrane PD-L1 in cancer patients remains controversial. In addition to membrane-associated PD-L1, tumor cell also secreted extracellular soluble PD-L1 in the microenvironment. However, even if extracellular soluble PD-L1 was detected, it did not solve the problem mentioned above. In the present study, we discovered another form of PD-L1 in extracellular microenvironment in cancer cells, that is exosomal PD-L1. However, the predictive role and the effect of tumor-derived exosomal PD-L1 is unclear. Methods: We evaluated the prognostic value of exosomal PD-L1 in the plasma of gastric cancer patients by ELISA and the effect of exosomal PD-L1-derived from gastric cancer cell lines by Western blot and Flow cytometry analysis. Results: Exosomal PD-L1 was detected in plasma samples from 69 gastric cancer patients, and exosomal PD-L1 content was significantly associated with T stage (P = 0.012). Overall Survival was significantly lower in the high exosomal PD-L1 group (p = 0.021). Additionally, gastric cancer cells also secreted exosomal PD-L1, with the amounts positively associated with PD-L1 amounts in the corresponding gastric cancer cell lines. Besides, exosomal PD-L1 was more stable and showed stronger immunosuppressive effects in the microenvironment compared with soluble PD-L1. Conclusions: Exosomal PD-L1 might predict the survival in gastric cancer, and induces higher T-cell apoptosis levels compared with soluble PD-L1.
Nano-liposomal irinotecan and 5-FU/LV (N+F) for the treatment of advanced PDAC: Memorial Sloan Kettering (MSK) Single Cancer Center Evaluation.
Authors: Glassman Danielle C. , Desai Avni Mukund , Ku Geoffrey Yuyat , Li Jia , Harding James J. , Varghese Anna M. , O'Reilly Eileen Mary , Yu Kenneth H.
Published: January 2019

471

Background: Therapy options for advanced pancreatic adenocarcinoma (PDAC) are finite. NAPOLI-1, a phase III randomized trial, demonstrated the efficacy of N+F following progression on gemcitabine (G) based therapy (mPFS 3.1 mo, mOS 6.1 mo). There are limited additional data on the safety and efficacy of N+F following FDA approval in October 2015. We examined the post approval safety, tolerability and effectiveness of N+F in advanced PDAC patients at MSK. Methods: A retrospective chart review was conducted of all patients treated with N+F from Feb 2016 and ending in Aug 2017. Using the EMR and institutional database, information was extracted pertaining to demographics, performance status (ECOG), prior therapies, dose, duration of N+F, adverse events, PFS, OS and treatment response per RECIST. Results:N = 56 identified. Demographics: M/F 29/27, age 68 (range 42-88), prior lines of palliative chemotherapy (0/1/2/3/ > 3, 4/20/21/11). Median PFS was 2.9 months and median OS was 5.3 months. There was a significant difference in PFS, OS and prior lines of therapy between patients who previously progressed on irinotecan (N = 27) versus not (N = 29); PFS = 2.4 v 4.8 mo, p = 0.0154; OS = 3.9 v 8.4 mo, p = 0.0021; 2 v 1 line. ECOG score was not predictive of PFS or OS. There were 19 dose reductions (DR), most frequent reasons: fatigue (42%) and diarrhea (37%). Regarding RECIST: PR = 2 (4%), SD = 19 (34%). 10/43 (23%) experienced > 50% CA 19-9 reduction. Dose reductions were not associated with worse outcomes, in fact, patients with 1 or more DR experienced significantly longer PFS v none (DR 2, not reached; DR 1, 5.2 mo; DR 0, 2.5 mo, p = 0.0185). For the subset who received sequential therapy with G+nab-paclitaxel (P) followed by N+F (N = 25) mOS of 25.4 mo. Conclusions: These data support the safety and efficacy of N+F, re-inforcing results of NAPOLI-1. Patients whose disease previously progressed on irinotecan fared significantly worse than patients who did not, when treated with N+F. N+F appears active even in patients requiring DR. Sequential therapy with G+P followed by N+F demonstrates encouraging mOS. Collectively these findings underscore the utility of N+F in the therapy of advanced PDAC.
Outcomes of locoregional treatment for unifocal progression in widespread metastatic gastroenteropancreatic neuroendocrine tumors.
Authors: Al-Toubah Taymeyah E. , Cives Mauro , Anaya Daniel A. , Soares Heloisa P. , Strosberg Jonathan R.
Published: January 2019

472

Background: New systemic treatments have improved the therapeutic landscape for patients with progressive, metastatic GEP-NETs. While drugs such as everolimus are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE), or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy, and sparing them toxicities of a new systemic treatment. Methods: We reviewed records of patients treated at a large referral center to identify patients seen between 1/2014 and 5/2017 with metastatic GEP-NETs who underwent a local treatment for focal progression. Patients undergoing lobar HAE or cytoreductive hepatic surgery were not included. The primary endpoint was time to new systemic therapy. Secondary endpoints included time to any additional intervention (systemic or local), progression free survival, and side effects of treatment. Results: 59 patients were identified who underwent a form of local treatment for a progressive metastatic tumor in the setting of widespread metastases. 27% underwent resection, 29% RFA, 25% external beam radiation, and 19% selective HAE. With a median follow-up of 17 months, 19 patients (32.2%) eventually progressed to the extent that they received salvage systemic treatment. 6 patients (10.2%) progressed and received further local treatment. Median time to new systemic treatment was 42 months (95% CI, 9.7-74.3 months). Median time to any additional intervention was 21 months (95% CI, 11.4-30.6 months). 4 patients died, all of whom had progressed and received further systemic treatment. Conclusions: We identified a large cohort of patients with metastatic GEP-NETs who underwent a local treatment for unifocal progression in the setting of widespread metastases. Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.
The impact of tumor genomic profile on the effectiveness of adjuvant chemotherapy in resectable intrahepatic cholangiocarcinoma.
Authors: Marcus Rebecca , Lillemoe Heather A. , Abdel-Wahab Reham , Shroff Rachna T. , Javle Milind M. , Aloia Thomas A.
Published: January 2019

474

Background: The incidence and mortality of ICC is rising in the U.S. While surgical resection currently offers the only potential for cure, the role of adjuvant chemotherapy is not well defined. Tumor genomic profiling is increasingly used to make adjuvant therapy decisions for malignancies. The purpose of this project was to evaluate the correlation between tumor genomic profile and the ability of adjuvant chemotherapy to prevent ICC recurrence after resection. Methods: A retrospective review of 49 patients with ICC undergoing surgical resection and comprehensive tumor genomic profiling was performed. The median age at diagnosis was 56 years (range: 21-72 yrs), 67% were female, and 67% were Caucasian. At resection, 20% had stage I disease, 43% stage II, 29% stage III, and 8% stage IV. Over 90% had moderately or poorly differentiated adenocarcinoma. Clinically relevant genetic mutations (those targeted by anticancer drugs currently on the market or required for entry into a mechanism-driven clinical trial) were evaluated using Foundation Medicine testing. Results: The median recurrence free survival (RFS) for the entire cohort was 9 months (range: 1-55 mo). 59% of patients received adjuvant chemotherapy – 66% gemcitabine-based treatment and 31% capecitabine-based. The most prevalent mutations were FGFR2 (28%), CDKN2A/B (24%), IDH1 (17%), and ARID1A (17%). Median RFS for the adjuvantly treated group was 12 months (range: 3-55 mo), and the presence of any clinically relevant mutation was associated with worse RFS (x vs. y, p = 0.03). IDH1 (30%), BAP1 (25%), and PBRM1 (20%) were most frequently mutated amongst patients who did not receive adjuvant therapy, and their median RFS was 5 months (range: 1-54 mo). Lack of an IDH1 mutation correlated with worse RFS (p = 0.02), while lower stage correlated with improved RFS (p = 0.01). Conclusions: For patients with ICC undergoing resection and adjuvant chemotherapy, the presence of clinically relevant genetic mutations is associated with reduced RFS. To gain further insight into the influence of tumor genomic profile on the effectiveness of adjuvant chemotherapy for this patient population, a multicenter collaborative effort is needed.
Association of adjuvant chemoradiotherapy with survival in patients with resected gallbladder carcinoma: A systematic review and meta-analysis.
Authors: Chie Eui Kyu , Kim Byoung Hyuck , Kwon Jeanny , Kim Kyubo
Published: January 2019

477

Background: The impact of adjuvant radiotherapy (ART) on survival in gallbladder carcinoma (GBC) remains underexplored, and conflicting results have been reported. We conducted a systematic review and meta-analysis to clarify the impact of ART in GBC. Methods: Systematic literature search was performed in the several databases following the PRISMA guidelines from inception to August 2016. We included the studies which reported survival outcome in the patients with or without ART following curative surgery. Results: Fourteen retrospective studies including 9364 analyzable patients met all inclusion criteria, but most of them had a moderate risk of bias. Generally, ART group had more patients with unfavorable characteristics than the surgery alone group. Nevertheless, pooled results showed that ART significantly reduced the risk of death (HR, 0.54; 95% CI, 0.44-0.67; p < 0.001) and recurrence (HR, 0.61; 95% CI, 0.38-0.98; p = 0.04) compared to the surgery alone group. Exploratory analyses demonstrated that subgroup of patients with lymph node positive disease (HR, 0.61; p < 0.001) and R1 resection (HR, 0.55; p < 0.001) had survival benefit from ART, while those with lymph node negative disease did not (HR 1.06; p = 0.78). No evidence of publication bias was found (p = 0.663). Conclusions: This work is the first meta-analysis evaluating the role of ART and provides convincing evidence that ART may offer survival benefit, especially in high risk patients. However, further confirmation with a randomized prospective study is needed to clarify the subgroup of GBC patients who would most benefit from ART.
Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study.
Authors: Pietge Heike
Published: January 2019

478

Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m2 gemcitabine and a fixed dose of cisplatin 25 mg/m2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.
Can looking at density differences between liver parenchyma and oligometastatic lesions predict outcomes and toxicities in patients receiving stereotactic body radiation therapy for metastatectomy?
Authors: Jin Will , Toesca Diego Augusto Santos , Osmundson Evan , Shaffer Jenny , Koong Albert , Chang Daniel Tandel
Published: January 2019

479

Background: Stereotactic body radiation therapy (SBRT) has found utility in oligometastatic liver lesions by providing excellent local control in most patients. These tumors are not routinely biopsied to evaluate for histologic grade due to high risk of seeding. Non-invasive pre-treatment radiographic findings may be able to identify a subset of patients at higher risk of local recurrence. Methods: Retrospective review of an IRB-approved database of liver metastases treated with SBRT yielded 55 patients for final analysis. Liver parenchyma and metastatic liver lesions were contoured using MIM version 6.6.5. Receiver Operating Characteristic curves and mean values were used to generate binary cutoffs for toxicities and Kaplan-Meier analysis, respectively. Computer Tomography features, like density, skew, kurtosis, variance, and volume, based on our pre-SBRT planning liver protocol images and their relationship with outcomes and toxicities were examined. Results: Largepre-SBRT density differences between oligometastatic lesions and liver parenchyma, as measured by Hounsfield Units, was associated with a 3.248 increased risk of local failures (p = 0.027) and grade 3 or higher late non-hepatobiliary toxicities (p = 0.032). There were no associations with overall survival. Lesions with large variance in density was associated with grade 3 or higher acute hepatobiliary toxicities (p = 0.043). Conclusions: Density metrics in metastatic liver lesions are readily available in most treatment planning systems and may be a prognostic indicator of tumor aggressiveness. Higher radiation doses may be needed to reduce rates of local recurrence in these patients. Further studies should examine if post-treatment density metrics are dose-dependent and correlate with outcomes.
The role of stereotactic body radiation therapy using the CyberKnife system in limited hepatic metastases.
Authors: ElAlfy Eman , Doyen Jerome , Bondiau Pierre-Yves
Published: January 2019

481

Background: CyberKnife has shown increasing evidence supporting its use for liver metastases with high rates of local control (LC) and low toxicity. we aim to investigate its safety and efficacy for patients with limited hepatic metastases. Methods: 48 patients (pts) with 63 metastatic liver lesions were treated with Cyberknife between March 2007 and November 2012. Most of pts were aged more than 65 years (ys) (n = 25) and males (n = 25). ECOG Performance status was 2 in 20 pts and 1 in 17 pts. Primary tumors were from GIT (n = 34), breast (6), ovary (2), choroidal melanoma (2), lung (1), kidney (1), thyroid (1) and CUP (1). Number of lesions treated per pt was 1 in 36, 2 in 9 and 3 in 3. GTV volume ranged from 0.81 to 164.07 cm³ (median = 22.53). Median volume of PTV was 23.73 cm³ and mean was 44.11 cm³ (range 2.03 - 215.40). We do not use margin (CTV = GTV). Dose per fraction ranged from 5 Gy to 15 Gy, median total dose was 43.5 Gy (range 25 - 45) in 3 fractions (3-5) and 143 beams prescribed to 80 % isodose line. The delivered median min GTV dose was 39.01 Gy and the prescribed median min PTV dose was 35.55 Gy. Results: Treatment was well tolerated with minimal grade 1 toxicity. 2 acute toxicities as nausea, asthenia and moderate colics. No Grade 3 or higher toxicity. Median follow-up was 11.9 months, overall survival (OS) was 83.6% and 57% at 1 and 2 yrs respectively, disease free survival (DFS) was 69.5% and 46.1% at 1 and 2 yrs and LC was 76.3% and 57.9% at 1 and 2 yrs. OS influenced by; Age < 65 years (P = 0.033), Males (P = 0.050), PTV volume < 50 cm3 (P = 0.002), Coverage > 95% for GTV (P = 0.041). Factors affected DFS were ; Age < 65 years (P = 0.034), Males (P = 0.017), Total dose of 45 Gy (P = 0.001), Dose per fraction equal to 15 Gy (P = 0.001), P.S = 2 (P = 0.024), Max dose > 55 Gy for GTV (P = 0.000), CTV (P = 0.000), PTV (P = 0.000), coverage > 95% for GTV (P = 0.048), CTV (P = 0.031), PTV (P = 0.001), min dose > 35 Gy for GTV (P = 0.032), CTV (p = 0.013), LC affected by; Females (P = 0.013). min dose > 35 Gy for PTV (P = 0.05). Conclusions: Cyberknife is an effective modality with good LC and minimal side effects for limited hepatic metastases. We recommend further studies to define the role of combined modality treatment, clarify treatment parameters and illustrate the related quality of life.
Patterns of failure in a phase II trial of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) for resectable and borderline resectable (BLR) pancreatic cancer.
Authors: Kharofa Jordan , Mierzwa Michelle Lynn , Olowokure Olugbenga Olanrele , Sussman Jeffrey J. , Latif Tahir , Gupta Anumeha , Esslinger Hope , Poreddy Sampath , Mcgill Brian , Wolf Eric , Smith Milton T , Choe Kyuran Ann , Ahmad Syed A.
Published: January 2019

482

Background: There is emerging interest in the role of SBRT in locally advanced pancreas cancer, however little prospective data exists examining the safety, efficacy, and optimal target volumes for SBRT in the neoadjuvant setting for resectable or BLR pancreatic cancer. Methods: Eighteen patients were enrolled from 11/2014-6/2017. SBRT was delivered to the tumor and abutting vessel with fiducials/compression and a 3 mm PTV margin to 33 Gy (6.6 Gyx5fxn) with an optional elective PTV to 25 Gy (5 Gyx5fxn) customized to the nodal space and mesenteric vessels. Patients without progression underwent surgery 4-6 weeks following SBRT. The primary endpoint is ≥ Grade 3 acute and late GI toxicity. Secondary endpoints included overall survival (OS), progression-free survival (PFS),and cumulative incidence of local failure (LF). LF is defined as recurrence within conventional RT volumes from the time of resection to local failure or last CT with no progression. Local failures were fused to planning CTs for dose quantification. Results: Thirteen patients had BLR tumors due to arterial abutment (n = 7) or SMV encasement (n = 8); 3 patients had resectable tumors. All patients received 4 months of gemcitabine/nab-paclitaxel (n = 13) or FOLFIRNOX (n = 5) prior to SBRT. There were no ≥ Grade 3 acute or late GI events. Metastases were noted in 6 patients (33%) at restaging or surgery. Surgery was performed in 12 patients (67%) with 11 (92%) R0 resections. Median OS and PFS are 21 months and 11 months, respectively. Progression occurred in 67% (8/12) of resected patients with first site of failure as distant (n = 3, 38%), local only (n = 4, 50%), and local and distant (n = 1,13%). The cumulative incidence of LF at 12 months from resection was 50%. All LF were outside to the PTV33 with median D90 of 11.5 Gy (4-25 Gy), V25 Gy of 51% (0-90%), and V33 Gy of 45% (0-52%). Conclusions: SBRT as a component of neoadjuvant therapy was well tolerated. However, local failures were predominantly observed outside the PTV33 volume within conventional RT volumes. Therefore, the durability of local control after SBRT in the neoadjuvant setting relative to chemoradiation merits close examination. Clinical trial information: NCT02208024.
Impact of molecular tumor board on late-stage gastrointestinal malignancies at a tertiary center.
Authors: Cannon Timothy Lewis , Murphy Jo-Ellen , Carter Jennifer , Trump Donald L. , Elkin Sheryl Krevsky , Asif Anam , Knopp Laura , Jessup John Milburn
Published: January 2019

483

Background: Inova Schar Cancer Institute formed a molecular tumor board in early 2016 to identify treatment options for patients with gastrointestinal malignances based on molecular testing and to track outcomes. Methods: From March 2016 to June 2017, 78 patients with advanced gastrointestinal malignancies were presented at our molecular tumor board. The most common mutations, the percentage of patients who received targeted therapies, responded to targeted therapies, died or went on hospice prior to receiving a recommended therapy, and had an available Association of Molecular Pathology Tier 1 or Tier 2 recommendation available were reviewed retrospectively. We also compared the overall survival of patients who received a new treatment after MTB compared to those who did not. N-of-One, Inc. provided curation of molecular testing and participated in the MTB. Results: 78 patients with gastrointestinal cancers were presented between March 2016 and June 2017. Thirteen (19%) patients received targeted therapy and 31% had partial response, 15% had Stable Disease, and 54% had progression of disease. 12 patients (15%) died or went on hospice before recommendations could start and 11 patients (14%) are waiting to start recommended therapy. 38 (49%) patients did not have a mutation that prompted a MTB recommendation. Median OS of the 33 patients who started a new therapy (including chemotherapy or unrelated clinical trials) after MTB was 15.3 months vs. 11.5 months in 40 patients who continued current therapy (P = 0.016 Wilcoxon). The three most common mutations detected were TP53, KRAS, and APC. The majority of cases had more than one variant. 18% of cases had a variant classified as Tier 1; 74% of cases had a variant with the highest AMP classification of Tier 2. Conclusions: The majority of patients with Gastrointestinal malignancies presented to the Inova MTB had a finding that supported a molecularly-guided therapy, with a small but meaningful number of partial responses. Barriers to the use of molecular guided therapy included molecular testing and presentation at a late disease stage, and alternative chemotherapeutic options.
Everolimus and transarterial embolization (TAE) for hepatic metastasis in neuroendocrine tumors (NET).
Authors: Chauhan Aman , Magee Gray , Horn Millicent , Khouli Riham , Weiss Heidi , Krohmer Steven J , Anthony Lowell Brian
Published: January 2019

485

Background: TAE of hepatic metastases is effective loco-regional therapy for neuroendocrine tumor (NET) patients. Transarterial chemotherapy (TACE) and transarterial radiotherapy (TARE) are other options in controlling hepatic metastases but deliver cytotoxic agents only at the time of the procedure. Systemic therapies such as everolimus or sunitinib are often held 2-4 weeks prior to and after the procedure. We hypothesize that concurrent oral treatment with everolimus and transarterial hepatic embolization is safe. Methods: Medical records of all NET patients (pts) treated at the Markey Cancer Center between July 2016 to July 2017 with concurrent transarterial embolization and everolimus were reviewed. Results: Total number of pts eligible for analysis was 15. Mean age of study cohort was 57.5 years (31-77). Seven pts were small bowel, 4 were pancreatic and remaining 4 were unknown NET primaries. Nine patients had grade 1 (Ki 67 < 2%) and 6 patients had grade 2 NETs (Ki-67 between 2-20%). Mean duration of treatment with everolimus prior to embolization was 3.8 months and mean dose was 10 mg orally every other day. Mean days of hospitalization were 1.46. Eleven (73%) pts were discharged the day after procedure. Ten (67%) pts reported nausea, 9 (60%) reported abdominal pain, 5 (30%) reported emesis. One patient had hematemesis immediately post procedure. Thirteen (87%) pts had no significant change in hemoglobin pre and post procedure (within one numerical point). No patient developed infectious complications. Conclusions: Combining everolimus with TAE is safe and does not result in longer hospitalizations or toxicities greater than that expected from TAE alone.
Palliative care and end-of-life health utilization in elder patients with pancreatic cancer.
Authors: Bhulani Nizar , Gao Ang , Gupta Arjun , Li Jenny Jing , Guenther Chad , Ahn Chul , Paulk M. Elizabeth , Houck Stephanie , Beg Muhammad Shaalan
Published: January 2019

488

Background: Prospective trials have shown that palliative care is associated with improved survival and quality of life, with lower rate of end-of-life health care utilization and cost. We examined trends in palliative care utilization in older pancreatic cancer patients. Methods: Pancreatic cancer patients with and without palliative care consults were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database between 2000 and 2009. Trend of palliative care use was studied. Emergency room and Intensive Care utilization and costs in the last 30 days of life were assessed. Statistical analyses were performed with SAS version 9.4 (SAS Institute, Inc., Cary, NC). Results: Of the 72205 patients with pancreatic cancer, 3383 (4.1%) received palliative care. The proportion of patients receiving palliative care increased from 1.8% in 2000 to 7.8% in 2009 (p for trend < 0.001). Patients with palliative care were more likely to be Asian and women. Of those who received palliative care, 73% received it in the last 30 days of life, and only 11% at least 12 weeks before death. The average number of visits to the ED in the last 30 days of life were significantly higher for patients who received palliative care (0.93±0.62) versus those who did not (0.79±0.61), p < 0.001, and had a significantly higher cost of care ($1317 vs $842, p < 0.001). Intensive care unit length of stay in the last 30 days of life did not differ between patients who did and did not receive palliative care (1.14 days vs 1.04 days, p 0.08). Intensive care unit cost of care was significantly higher for patients with palliative care compared to their counterparts ($5202.641 vs $3896.750, p < 0.001). Conclusions: Palliative care use for pancreatic cancer patients has increased between 2000 and 2009 in this study of Medicare patients. However, it was largely offered close to the end of life and was not associated with reduced health care utilization or cost. Early palliative care referral may be more beneficial.
The pathway regulating RhoA activity to predict the survival of gastric cancers.
Authors: Gao Jing , Huang Wenwen , Mu Shuo , Zhao Songhui , Zhang Shuirong , Zhang Peng , Ge Sai , Li Zhongwu , Zhang Cheng , Yao Ming , Liu Zhenzhen , Wang Kai , Shi Weiwei , Shen Lin
Published: January 2019

49

Background: RhoA mutation has been intensively studied for its association with progression in gastric cancer (GC). Recently, mutations in a pathway regulating RhoA activity have been identified as a predictive biomarker in breast cancer. Herein, our aim is to investigate the role of such pathway in the progression of patients with GC receiving chemotherapies. Methods: Two non-overlapped TCGA cohorts (TCGA1, downloaded from GDC, N = 123 and TCGA2, from Cbioportal, N = 312) and a third ACRG cohort (Nature Medicine 2015, N = 295) were assessed for their mutation status of RhoA pathway; meanwhile, a cohort from Chinese GC (CGC, N = 57) was examined with whole exome sequencing (WES). A subset of “Regulation of RhoA activity” pathway (NCI Pathway Interaction), denoted as RhoA_S, was derived from analyzing the expression of RhoA and mutations in TCGA1 without referring to its survival data. Subsequently, RhoA_S was evaluated for its prediction of overall survival (OS) in the above four GC cohorts receiving chemotherapies. Results: GCs with wild-type of RhoA_S as well as gain-of-function of RhoA mutation where the function of RhoA remained active were compared against those with mutated RhoA_S. The frequencies for the mutant RhoA_S were 46.3%, 24.0%, 16.3% and 50.9% for TCGA1, TCGA2, ACRG and CGC, respectively; while the “active” RhoA_S were found more unlikely to respond to chemotherapies and significantly associated with poor clinical outcomes in all four cohorts. The hazard ratios and p-values were 0.513, 0.009 for TCGA1; 0.509, 0.02 for TCGA2; 0.6, 0.04 for ACRG and 0.229, 0.014 for CGC, respectively. Conclusions: Four independent GC cohorts (totally 787 patients) validated RhoA_S as a predictive biomarker for their survival. Not only have our results confirmed gain-of-function in RhoA mutant facilitates the progression of GC patients, but also indicated the regulators of RhoA activity are implicated in their overall survival. This study has provided us an option to extend potentially druggable targets in highly malignant cancers with poor prognosis like GC.
Retrospective single center review of toxicity and efficacy of a modified FOLFIRINOX regimen in patients with locally advanced and metastatic pancreatic cancer.
Authors: Pulluri Bhargavi , Skelly Joan , Barry Maura Meredith
Published: January 2019

490

Background: Conroy et al. (N Engl J Med 364:1817–1825, 2011) have shown significantly better overall survival with FOLFIRINOX compared to gemcitabine in metastatic pancreatic cancer patients (MPC). However, given the toxicity associated with FOLFIRINOX treatment, different institutions have adapted varying modifications to the original regimen. Methods: We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in patients with unresectable locally advanced pancreatic cancer (LAPC) and MPC treated between Jan 2011 and Dec 2015 at University of Vermont Medical Center. Results: 43 patients were treated, of which 33 did not receive any prior treatment (6 LAPC, 27 MPC). 41 patients received dose attenuation with 1st cycle. Median relative dose of irinotecan, oxaliplatin and 5-FU were less than reported by Conroy (69 vs. 81%, 70 vs. 78% and 71 vs. 82%). Median number of treatment cycles 7.8 (range 1 to 41). Median progression free survival in our MPC cases compared to Conroy’s data was 5.7 vs. 6.4 months; overall survival at 6 and 12 months were 78 vs. 75.9% and 41 vs. 48.4% respectively. Grade ¾ toxicities were less, including neutropenia (p<0.001), fatigue (p =0.01) and neuropathy (p=0.04). One patient had grade 3 pneumonitis related to oxaliplatin. Conclusions: Our findings suggest that dose attenuation of 5-FU, irinotecan and oxaliplatin improve tolerability with fairly similar outcome as reported by Conroy et al. [Table: see text]
Is there any survival benefit of additional chemotherapy (C) following adjuvant C in pancreatic cancer (PC) patients (pts) with postsurgery elevated CA19-9?
Authors: Saif Wasif M. , Smith Melissa H , Goodman Martin D. , Russo Suzanne M. , Huber Kathryn , Salem Ronald R
Published: January 2019

491

Background: Pancreatectomy offers only potential for cure but is only possible in a minority of pts. Even in those pts who receive adjuvant C, majority of them succumb to death due to metastases. RTOG 9704 showed that post-surgery CA 19-9 levels are an important predictor of survival. ESPAC-3 showed that completion of all 6 cycles of adjuvant C was an independent prognostic factor. Any survival benefit of an intensified C strategy has not been demonstrated in pts with persistently ↑ CA19-9. The object of this study was to investigate any benefit of additional C following adjuvant in these pts. Methods: 25 pts with R0 surgery of PC who received adjuvant C with post-surgery ↑ CA 19-9 but no radiographic evidence of cancer were identified between 2005-2017. Either biopsy or PET scan determined recurrence of PC. Efficacy endpoints were overall survival (OS) and disease-free survival (DFS). Results: The Table summarizes results. Additional C included 5-FU, capecitabine, platins, irinotecan and nab-paclitaxel. CA 19-9 normalized in 3 pts while 22 remained ↑ or further ↑. Two pts underwent metastatectomy. Median DFS was 14.5m (9-18), OS 29m (19-96) and OS rates were 80 %, 50 % at 1 and 2 years respectively. Conclusions: We believe that the longer OS of our pts with ↑ CA 19-9 post-surgery was due to additional C following adjuvant C, close monitoring with monthly CA19-9 and 3-monthly CT scans. Our study also underlines importance of collecting pre-surgery CA19-9 and complete staging including chest. Prospective study aiming to evaluate role of maintenance or intensified C are indicated.[Table: see text]
The relationship between dose to skeletal muscle area ratio and gemcitabine nab-paclitaxel toxicity in pancreatic ductal adenocarcinoma.
Authors: Wong Rachel , Freckelton Julia , Croagh Daniel , Holt Darcy Quinn , Fox Adrian , Lee Margaret , Moore Gregory Thomas
Published: January 2019

492

Background: Combination gemcitabine and nab-paclitaxel (Gem-Nab-P) is a common regimen used to treat metastatic pancreatic ductal adenocarcinoma (PDAC). Toxicity is less than that associated with other combination metastatic regimens (FOLFIRINOX), but it is still associated with significant morbidity. Currently, Gem-Nab-P is dosed using estimated body surface area. This study investigates whether skeletal muscle assessment could be a useful tool in the dosing of Gem-Nab-P in metastatic PDAC. Methods: This study involved two sites and included patients who had received Gem-Nab-P between January 2013 and March 2017. A review of medical records was used to identify demographic, disease and first-cycle treatment information. Chemotherapy toxicity was defined as grade 3 or 4 adverse events using the National Cancer Institute Common Toxicity Criteria Adverse Events manual v4.0. Body composition analysis was performed on computed tomography scans at spinal level L3, using SliceOmatic software. SPSS software was used to for all statistical analysis, with a p value of < 0.05 considered significant. Results: We identified 52 patients treated with first-line Gem-Nab-P for PDAC. Median age was 65 years (57-73) and 24 (47%) were male. Median BMI at commencement of Gem-Nab-P was 24.7 kg/m2 (21.3-27.4) and 38 (58%) of the patients were myopenic before starting chemotherapy. Fourteen (27%) patients experienced toxicity during the first cycle of chemotherapy. Patients who experienced first-cycle chemotherapy-associated toxicity did not have a different median SkMA to those who did not (128.6 cm2 vs. 111.4 cm2, p= 0.2). There was also no difference in the gemcitabine dose to SkMA ratio (14.1 mg/cm2 vs. 14.4 mg/cm2, p=0.8), nab-paclitaxel to SkMA ratio (1.8 mg/cm2 vs. 1.8 mg/cm2, p=0.6) or combined dose equivalent to SkMA ratio (2.8 mg/cm2 vs. 2.9 mg/cm2, p=0.9) between the patients that experienced first cycle toxicity versus those that did not. Conclusions: This study suggests that a pancreatic cancer patient’s skeletal muscle area is unlikely to be a useful addition to conventional body surface area in the dosing of first line Gem-Nab-P, to reduce first-cycle toxicity.
Indoleamine 2,3-dioxygenase (IDO1), PD-L1, and overall survival (OS) of patients diagnosed with esophageal cancer.
Authors: Rosenberg Ari , Wainwright Derek , Rademaker Alfred , Galvez Carlos , Genet Matthew , Zhai Lijie , Lauing Kristen , Villaflor Victoria Meucci
Published: January 2019

50

Background: Immune checkpoint inhibition of PD-L1 is emerging as an important therapeutic target for patients with advanced esophageal cancer. However, response rates to therapy remain low. IDO1 is a rate-limiting immunosuppressive enzyme that has emerged as an important immunotherapeutic target in human cancer. The role, expression pattern, and relevance of IDO1 in esophageal cancer are currently unknown. Here, we utilize gene expression analysis of the cancer genome atlas and quantitative immunohistochemistry (IHC) to understand whether IDO1 contributes to a poor esophageal cancer patient prognosis. Methods: mRNA expression was assessed using Hi-RNA sequencing in an esophageal squamous cell carcinoma (SCC) cohort of 87 patients and an adenocarcinoma (AC) cohort of 97 patients. Survival data was obtained from the Cancer Genome Atlas. Patient survival was analyzed by the Kaplan-Meier Method. IHC for a second cohort of 93 cases of esophageal SCC were stained for IDO1, PD-L1, and CD3ε, followed by light microscopic immunoscoring analysis. Correlation between markers was analyzed using Fisher’s exact test. Results: The median OS for high versus low IDO1 mRNA levels was 15.9 months vs 41.5 months, respectively (p =0.02) in the SCC cohort. The median OS was 20.1 months and 58.6 months in the high vs low IDO1 mRNA levels, respectively (p = 0.036) in the esophageal AC cohort. High co-expression for IDO1 and PD-L1 vs low co-expression of these markers, demonstrated a median OS of 15.1 months and 41.5 months, respectively, in the SCC cohort, and 13.7 months and 41.5 months, respectively, in the AC cohort. IHC for IDO1 SCC showed a significant correlation with PD-L1 (p = < 0.0001) and CD3ε (p = < 0.0001). PD-L1 expression also significantly correlated with CD3ε expression (p = < 0.0001). Conclusions: Esophageal cancer with high IDO1 and PD-L1 levels is associated with significantly decreased survival. The expression of IDO1 and PD-L1 is significantly enhanced by the coincident intratumoral increase of T cells. These data suggest that combinatorial approaches for combination therapies that simultaneously inhibit IDO1 and PD-(L)1 may enhance T-cell mediated control of esophageal cancer in patients.
Neoadjuvant therapy outcomes in nonmetastatic pancreatic cancer.
Authors: Muniz Kovtun Jeanette , Kovtun Konstantin , Mortele Koenraad , Moser James , Bullock Andrea J.
Published: January 2019

501

Background: The optimal multidisciplinary treatment algorithm for pancreatic ductal adenocarcinoma (PDAC) is not well established. We studied outcomes in non-metastatic PDAC treated with chemotherapy and stereotactic body radiation therapy (SBRT) with or without pancreatic resection. Methods: Between August 2011 and July 2015, 73 patients with non-metastatic PDAC were treated with chemotherapy and SBRT with or without resection. Variables considered included: ECOG, CA 19-9, clinical stage, vascular involvement, pathologic stage and margin status. Resectability status was determined by an expert abdominal radiologist on initial staging imaging. Chemotherapy included FOLFIRINOX, FOLFOX, gemcitabine monotherapy (gem) or with nab-paclitaxel (gem/nab). SBRT was delivered as 30 Gy in 3 fractions over 5 days via CyberKnife. The Kaplan-Meier method and log-rank test were used to compare median overall survival (mOS), local progression free survival (LPFS) and metastasis free survival (MFS). Results: After a median follow-up of 19.3 months (mo) the mOS was 30.0 mo (95% CI, 19.4 to 36.5). The surgical group had longer mOS (36.5 vs 19.4 mo; P < 0.001), LPFS (29.0 vs 16.3 mo; P = 0.03) and MFS (29.0 vs 15.1 mo; P < 0.001) as compared to the nonsurgical group. FOLFIRINOX or gem/nab was associated with better mOS as compared to other chemotherapy (33.2 vs 12.8 mo; P < 0.001). There was a trend towards longer mOS in pts with initial imaging deemed less resectable (36.5 vs 30.1 vs 13.0 mo in unresectable vs borderline vs resectable; P = 0.19). In a multivariate analysis significant predictors of OS were resection, ECOG and FOLFIRINOX or gem/nab chemotherapy. Conclusions: Patients who had surgery after neoadjuvant chemotherapy and SBRT had significantly longer mOS, LPFS and MFS than those without surgery. FOLFIRINOX or gem/nab and better ECOG were also associated with improved outcomes. Worse resectablity status per imaging was associated with longer OS despite less likelihood of surgery; This may reflect more intensive neoadjuvant therapy or suggest that radiologic resectability status is a poor predictor of OS. Further investigation of factors underlying this discrepancy may have implications on neoadjuvant strategy and resectability determination.
Survival outcomes among patients with advanced hepatocellular carcinoma (aHCC) treated with systemic therapies.
Authors: Bonafede Machaon , Cai Qian , Singh Prianka , Jariwala-Parikh Krutika , Cappell Katherine , Parikh Neehar D. , Sill Bruce , Korytowsky Beata
Published: January 2019

503

Background: HCC is the most common primary liver cancer. Despite the wide use of screening among high-risk individuals, about 45% of cases are diagnosed at the advanced stage. Sorafenib is the only FDA-approved first-line (1L) treatment for aHCC. This study aims to characterize survival by lines of therapy among commercially insured patients with aHCC treated with systemic therapy in the United States. Methods: Adults with ≥ 2 medical claims (30–180 days apart) for primary HCC ( ICD-9 155.0x) from 1/1/2008 to 9/30/2015 were identified in the MarketScan Research Databases. Continuous enrollment was required 6 months before and 1 month after diagnosis. Patients were further categorized into 1L and 2L cohorts if they initiated a targeted therapy, immunotherapy, or chemotherapy. Index date of 1L was the date of the first claim for a systemic agent after diagnosis; index date of 2L was the date of the first claim for a different agent after the end of 1L therapy. Date of death was determined based on records from the linked Social Security Administration Master Death File or on inpatient discharge status. Survival time was measured from the 1L/2L index date to the death date; patients without a death date were censored at end of continuous enrollment or study period, whichever occurred first. Results: 758 patients met the selection criteria for the 1L cohort (mean age, 62.5 ± 10.3 y; 21.9% female); 87 patients (11.5%) went on to receive 2L therapy (mean age, 61.8 ± 9.8 y; 20.7% female). Over half the patients (1L, 54.0%; 2L, 52.9%) died during the follow-up period; median survival time was 205 days (interquartile range [IQR], 290 days) in 1L patients and 280 days (IQR, 232 days) in 2L patients. 32.6% of 1L patients and 34.5% of 2L patients survived ≥ 1 year, and 12.4% of 1L patients and 16.1% of 2L patients survived ≥ 2 years after treatment initiation. Conclusions: Findings suggest that the vast majority of patients with aHCC do not receive 2L therapy. A high 1-year mortality rate represents the lack of effective treatment options in aHCC. Improved therapies are urgently needed for this highly morbid malignancy.
Role of FDG PET/CT scan in preoperative pancreatic cancer staging.
Authors: Ghanta Bhargavi , Thambi-Pillai Thavam C. , Timmerman Gary , Fischer Christopher , Nelson Annie , Bleeker Jonathan Scott
Published: January 2019

511

Background: Guidelines do not recommend routine FDG PET/CT (PET) as preoperative staging for pancreatic cancer, although many single center series have demonstrated that PET can lead to changes in management in a sizable minority of patients. We performed a retrospective analysis of patients undergoing PET for potentially resectable pancreatic adenocarcinoma at our institution to help define the utility of PET in this setting. Methods: We reviewed patients with pancreatic adenocarcinoma diagnosed at our center from June 2010 to May 2017 and included patients with pancreatic adenocarcinoma felt to be potentially resectable following standard staging studies [computed tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS)] who also underwent preoperative PET. Data collected and analyzed included: demographics, pre-PET staging, CA19-9 levels, PET results and surgical outcomes. Results: Forty eight patients with pancreatic adenocarcinoma felt to be surgically resectable underwent PET. PET changed management in 4/48 (8.3%) of these patients. In all 4 of these patients, hepatic metastatic disease was detected on PET and planned surgery was canceled; metastatic disease was confirmed by biopsy in 1 of these patients. 1/48 (2.1%) of patients had a false positive PET scan, where a focus of suspected metastatic disease on PET was biopsied and found to be benign, allowing the patient to proceed to surgery. 3/48 (6.3%) of patients had a false negative PET; 2 patients had hepatic metastatic disease and one had peritoneal disease discovered during surgery. Mean time from negative PET to surgery in these 3 patients was 31 days (range 21-45). Degree of CA19-9 elevation and primary tumor FDG avidity did not correlate with detection of metastatic disease on PET. Conclusions: PET changed management in a smaller number of patients in this cohort than in many previously reported series with a nearly equal number of patients with false negative PET results proceeding to unnecessary surgery. These results are consistent with the currently uncertain role of PET in preoperative staging for pancreatic cancer and further work must be undertaken to optimize presurgical staging in this population.