bluuebunny/crossref_metadata_2025 huggingface dataset:
Update result of HGCSG 1403: Phase I trial of oxaliplatin/irinotecan/S-1 (OX-IRIS) as first-line chemotherapy for unresectable pancreatic cancer.
Authors: Nakano Shintaro , Kawamoto Yasuyuki , Yuki Satoshi , Yagisawa Masataka , Sawada Kentaro , Muranaka Tetsuhito , Nakatsumi Hiroshi , Saiki Takuro , Ishiguro Atsushi , Harada Kazuaki , Kobayashi Yoshimitsu , Iwanaga Ichiro , Hatanaka Kazuteru , Sakata Yuh , Komatsu Yoshito
Published: January 2019

359

Background: FOLFIRINOX has become one of the standard treatment for unresectable pancreatic cancer with distant metastasis. OX-IRIS is the combination therapy of oxaliplatin (L-OHP), irinotecan (IRI) and S-1. It is the useful treatment to dispense with a continuous infusion of 5FU by administering S-1 orally. For establishing OX-IRIS therapy as a new standard treatment, we planned this study for evaluating dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: This study was carried out as a multicenter phase I study. Chemotherapy-naïve patients with unresectable pancreatic cancer were included. L-OHP and IRI were administered on day 1 and 15, and S-1 was taken twice a day in day 1-14, and then 14 days were rest for 1 cycle. The primary endpoints were the frequency of DLT and estimating of MTD. Secondary endpoints were safety, response rate, progression-free survival (PFS) and overall survival (OS). Results: Between January 2016 and August 2017, 13 cases were enrolled. The patients’ backgrounds were median age 62; male /female, 9/4; the primary tumor sites head /body and tail, 8/5; ECOG PS 0/1, 7/6; UR-LA /UR-M, 4/9. Two of five enrolled in level 0 (L-OHP: 85 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. One of six in level -1 (L-OHP: 65 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. At level 0, 100% of cases had anemia and fatigue, 80% anorexia, diarrhea, peripheral sensory neuropathy, 60% platelet count decrease. At level -1, 100% had anemia, 75% nausea and fatigue, 63% anorexia. Response rate was 10% and disease control rate was 70% in ten cases with evaluable lesion. Median PFS was 4.1 months (95%C.I.; 0.0-8.6 months). Median OS was 13.7 months (95%C.I.; 5.9-21.5 months). Conclusions: In this study, MTD was estimated to be level 0, and determined recommended dose is level -1 for the planned future study. We are going to evaluate efficacy and safety in a phase II study. (UMIN ID: 000017002) Clinical trial information: 000017002.
FOLFIRINOX in pancreatic cancer patients age 75 years or older.
Authors: Mizrahi Jonathan , Rogers Jane , Hess Kenneth R. , Wolff Robert A. , Varadhachary Gauri Rajani , Shroff Rachna T. , Ho Linus , Fogelman David R. , Raghav Kanwal Pratap Singh , Overman Michael J. , Pant Shubham
Published: January 2019

362

Background: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS) (11.1 vs 6.8 months [m] with gemcitabine, P < 0.001), pts > 75 yrs old were excluded from this study. As per SEER 2011-2015 data, 38% of new PC cases are diagnosed in pts age > 75. The purpose of this study was to assess the safety and efficacy of FOLFIRINOX in this group of pts. Methods: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with FOLFIRINOX at MD Anderson since 2011. Data obtained include demographics, line of treatment (tx), starting dose, progression free survival (PFS), OS and toxicities. Response was determined by chart documentation. Primary outcomes were mOS and rates of grade 3/4 hematologic toxicity (HT). Results: A total of 24 pts (19 male) were included with median age of 76 (range 75 to 84). 18 had metastatic disease, and FOLFIRINOX was the 1st line of tx for 18 of the 24 pts. The median number of cycles administered was 4 (range 1 to 12). The most frequent starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Bolus 5-FU and leucovorin were omitted in all but 3 pts. Median PFS was 3.7 m (95% CI: 3.0-5.7) with mOS of 11.6 m (95% CI: 6.14-15.7). 16 pts (67%) experienced disease control (response to tx or stable disease). Grade 3 or 4 HT occurred in 11 pts (46%), and 9 (38%) were supported with granulocyte colony-stimulating factor at some point during tx. 6 pts (25%) required hospital admission for any toxicity, most commonly infection (3 pts), and 10 (42%) stopped FOLFIRINOX due to toxicity, most commonly fatigue (6 pts). Conclusions: In this single-center retrospective analysis of 24 unresectable PC pts age 75 or older given FOLFIRINOX, OS outcomes were similar to those reported by Conroy et al in the original trial which excluded pts older than 75. In our review, toxicities including incidences of grade 3 or 4 HT were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar efficacy and toxicity when compared to younger pts.
Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: Results of Part A (pembrolizumab alone).
Authors: Mulvey Claire , Raj Nitya Prabhakar , Chan Jennifer A. , Aggarwal Rahul Raj , Cinar Pelin , Hope Thomas A , Kolli Kanti , Zhang Li , Calabrese Susan , Grabowsky Jennifer Ann , Modarresi Lila , Kelly Virginia , Stonely Danielle , Munster Pamela N. , Reidy Diane Lauren , Fong Lawrence , Bergsland Emily K.
Published: January 2019

363

Background: Immune checkpoint inhibitor (CPI) efficacy has not been established in extrapulmonary poorly-differentiated neuroendocrine carcinomas (EP-PDNECs). In small cell lung cancer, promising antitumor activity of CPI led to accelerated approval of nivolumab in 8/2018. We investigated the efficacy and safety of pembrolizumab (PEM)-based therapy in biomarker-unselected EP-PDNECs. Methods: Open label, multicenter, phase 2 study of PEM-based therapy in patients (pts) with EP-PDNECs, excluding Merkel cell carcinoma and well differentiated grade 3 NET, with progression on first-line systemic therapy, ECOG 0-1, and adequate hepatic and renal function. Enrollment via an adaptive Simon’s 2-stage design. Plan for 14 pts treated with PEM alone (Part A Stage 1) 200 mg IV every 3 weeks. If > 2 of 14 pts respond by week 18, then 21 additional pts enroll in Part A Stage 2, corresponding to H0 10% vs. H1 26% response rate (RR) at type I error 0.05 with power 80%. Otherwise study proceeds to Part B: PEM plus chemotherapy (dealer's choice of weekly irinotecan or paclitaxel). Primary endpoint is objective RR (ORR) by RECIST 1.1. Secondary endpoints include safety, overall survival, and progression-free survival (PFS). Serial blood samples and baseline tumor biopsies required in all pts for future biomarker studies. Results: Preliminary data from Part A Stage 1 are available. Of 14 pts enrolled, male/female 9/5; median age 63; 1 large cell, 11 small cell, 2 NOS. Primary site of disease: GI 43%, GU 29%, and other 29%. Median Ki67 80% (available for 9 pts). Best response: CR (1), PR (0), SD (2), PD (10), unevaluable (1; early death from sepsis) for ORR 7%. Median PFS was 58 days. Six (43%) pts went off study for early PD or clinical deterioration before first scheduled scan at 9 weeks. PEM was well tolerated with no grade 3-5 AEs attributed to therapy. At last follow up, 9 (64%) pts were alive with 1 pt still on treatment after 19 cycles. Conclusions: PEM monotherapy was not effective in this pretreated, biomarker-unselected population of EP-PDNECs arising in different organs. Part B (PEM plus chemotherapy) enrollment is ongoing. Biomarker studies are planned (Parts A/B). Clinical trial information: NCT03136055.
The influence of renal function on gemcitabine-based chemotherapy for advanced biliary tract cancer: An exploratory subgroup analysis of JCOG1113.
Authors: Ueno Makoto , Morizane Chigusa , Okusaka Takuji , Ogawa Gakuto , Sato Yuya , Ikeda Masafumi , Ozaka Masato , Sugimori Kazuya , Fukutomi Akira , Hara Hiroki , Mizuno Nobumasa , Yanagimoto Hiroaki , Sano Keiji , Tobimatsu Kazutoshi , Yane Kei , Nakamori Shoji , Sata Naohiro , Nishina Tomohiro , Ishii Hiroshi , Furuse Junji
Published: January 2019

368

Background: JCOG1113 is a randomized phase III trial to evaluate gemcitabine (GEM) plus S-1 (GS) versus GEM plus cisplatin (GC) regarding overall survival (OS) for advanced biliary tract cancer (BTC) (UMIN000001685) and the non-inferiority of GS was demonstrated. It is necessary to consider renal function using cisplatin or S-1 because cisplatin has renal toxicity, and the toxicity of S-1 is affected by renal function. Therefore, we evaluated the influence of renal function on the efficacy and safety of GC and GS in JCOG1113. Methods: All enrolled patients (pts) in JCOG1113 (n = 354) were analyzed. Eligibility criteria included chemotherapy-naïve pts with recurrent or unresectable biliary tract adenocarcinoma, ECOG-PS of 0–1, CCr > 50 ml/min, and adequate organ function. Renal function was classified into two groups by creatinine clearance (CCr) as calculated by the Cockcroft-Gault formula; high CCr (CCr ≥ 80 ml/min) or low CCr (80 > CCr ≥ 50 ml/min). The impact of renal function on OS and progression-free survival (PFS) were compared using the Cox regression model. The adverse events (AEs) were compared using Fisher’s exact test. Results: Eighty-eight pts on GC and 88 pts on GS were included in the high CCr group, and 87 pts on GC and 91 pts on GS were included in the low CCr group. There were no differences between the groups regarding, sex, PS, primary site, biliary drainage, operation, or recurrence, except for age. The hazard ratio (HR) of GS to GC for OS was 1.12 (95% CI 0.81–1.56) in the high CCr group and 0.80 (95% CI 0.58–1.11) in the low CCr group. The HR of GS to GC for PFS was 1.06 (95% CI 0.78–1.44) in the high CCr group and 0.69 (95% CI 0.50–0.94) in the low CCr group. Grade 3-4 AEs of white blood cell count decreased (35.3%/23.6%), anemia (29.4%/7.9%) and platelet count decreased (18.8%/10.1%) were more common in GC than GS in the low CCr group. In contrast, the incidence of all grade 3-4 non-hematological AEs was higher (36.0%/11.8%) in GS than GC in the low CCr group ( p = 0.0002). Conclusions: GS was better in terms of OS, PFS, and hematological toxicities than GC in the low CCr group. GS might be recommended for the population with lower renal function in the treatment for advanced BTC.
Impact of initial imaging with gallium-68 dotatate PET/CT on diagnosis and management of patients with neuroendocrine tumors (NETs): A sequential case series.
Authors: Kennecke Hagen F. , Raghu Preethi , Lin Bruce , Funk Gayle L. , Alseidi Adnan , Hubka Michal , Rosales Joseph G , Rocha Flavio G. , Lee Marie E.
Published: January 2019

379

Background: Somatostatin analogue functional imaging with Ga-68 Dotatate PET/CT has demonstrated superiority in lesion detection in patients with NETs. The effect of this novel imaging modality on US clinical practice and its usefulness in different types of NETs is not well described. We describe the impact of initial NETSPOT imaging on diagnosis and management in NET patients at a large urban medical center. Methods: Consecutive patients diagnosed with NETs and referred to our institution who received an initial Ga-68 Dotatate PET/CT between 07/2017-09/2018 were included. Imaging was reviewed and compared to prior available CT, MRI, and/or In-111 Pentetreotide scans. Results: Among 101 patients, 51/50 were female/male, tumor origins were gastroenteropancreatic (GEP) (75%), Unknown Primary (UP) (13%), lung (8%), thymic (2%), and other (2%). All tumors were histologically well/moderately differentiated and 37/51/3/10 were G1/G2/G3/Unknown, respectively. Initial imaging with Ga-68 Dotatate PET/CT revealed additional metastatic disease in 37 of 77(48%) patients with prior evidence of metastatic disease. Most common sites were distant lymph nodes (18), bone (15) and liver (9), peritoneal/pleural (4). A previously UP tumor was identified in 3 patients. No patients with metastatic lung carcinoids (6 atypical, 2 typical) or thymic NETs (2 atypical/G2) NETs had evidence of Ga-68 Dota PET/CT uptake above reference liver SUV levels. Results of imaging altered patient management as follows: 14 initiated systemic therapy due to documentation of progression, in 6 surgical therapy was altered, in 4 biopsy/other management was changed. In 11 patients with no tumor Ga-68 Dotatate uptake, decisions about use of PRRT and somatostatin analogues was altered. Conclusions: In this series, Ga-68 Dotatate PET/CT altered diagnosis and management in 35/101 NET patients. Among GEP and UP NETs, Dotatate imaging diagnosed primarily new nodal, bone, liver and pleural/peritoneal metastases missed by other imaging modalities. Results support the routine use of Ga-68 Dotatate PET/CT in the care of patients with advanced and early stage NETS.
Differences in overall survival for patients with cholangiocarcinoma: Racial/ethnic disparity or socioeconomic factors?
Authors: Lee Rachel M , Liu Yuan , Zaidi Mohammad Yahya , Gamboa Adriana Carolina , Russell Maria C. , Cardona Kenneth , Maithel Shishir K.
Published: January 2019

380

Background: Inequities in cancer survival are well documented. Whether disparities in overall survival (OS) result from inherent racial differences in underlying disease biology or socioeconomic factors (SEF) is not known. Our aim was to define the association of race/ethnicity and SEF with OS in pts with cholangiocarcinoma (CCA). Methods: Pts with CCA of all sites and stages in the National Cancer Data Base (2004-14) were included. Racial/ethnic groups were defined as non-Hispanic White (NH-W), non-Hispanic Black (NH-B), Asian, and Hispanic. Income and education were based on census data for pts’ zip code. Income was defined as high (³$63,000) vs low ( < $63,000). Primary outcome was OS. Results: 27,151 pts were included with a mean age of 68 yrs; 51% were male. 78% were NH-W, 8% NH-B, 6% Asian, and 6% Hispanic. 56% had Medicare, 33% private insurance, 7% Medicaid, and 4% were uninsured. 67% had high income. 21% lived in an area where > 20% of adults did not finish high school. NH-B and Hispanic pts had more unfavorable SEF including uninsured status, low income, and less formal education than NH-W and Asian pts (all p < 0.001). They were also younger, more likely to be female and to have metastatic disease (all p < 0.001). Despite this, NH-B race and Hispanic ethnicity were not associated with decreased OS. Male sex, older age, non-private insurance, low income, lower education, non-academic facility, location outside the Northeast, higher Charlson-Deyo score, worse grade, larger tumor size, and higher stage were all associated with decreased OS (all p < 0.001). On MV analysis, along with adverse pathologic factors, type of insurance (p = 0.003), low income (p < 0.001), and facility type and location of treatment (p < 0.001) remained associated with decreased OS; non-white race/ethnicity was not. Conclusions: Disparities in survival exist in CCA, however they are not driven by race/ethnicity. Non-privately insured and low-income pts had decreased OS, as did pts treated at non-academic centers and outside the Northeast. This suggests that decreased ability to access and afford care results in worse outcomes, rather than biological differences amongst racial/ethnic groups.
Gemcitabine, docetaxel, and capecitabine (GTX) as a first-line regimen in metastatic pancreatic adenocarcinomas (mPAC): A single institution experience.
Authors: Singh Vikas , Sharma Vivek R.
Published: January 2019

385

Background: After decades of minimal to no therapeutic options, Gemcitabine emerged as the only safe & effective frontline regimen for mPAC. A 3-drug combination regimen, GTX, first optimized by Fine et al in 2009 showed improved progression free (PFS) & median overall survival (mOS) based on a multicentric prospective phase II study. It didn’t receive much wider acceptance likely due to lack of phase III data and emergence of newer regimens such as Gemcitabine plus nab-Paclitaxel (GA) and FOLFIRINOX (FFX). We reviewed our institutions experience with GTX and other regimens in mPAC patients. Methods: We performed a retrospective review of clinical outcomes in patients diagnosed with mPAC between January 2005 and December 2015 and treated at our institution. Attempts were made to include all eligible patients to reduce any selection bias. Results: Fifty patients with mPAC were analyzed for mOS and toxicities with different regimens. 50% patients received GTX while remaining received – FFX (22%), Gemcitabine (14%), GA (4%), FOLFOX (4%) & other (6%) regimens. The mOS for all the patients was 7.67 months (95% CI 5.98-10.81). The mOS was significantly improved in patients who received GTX as first line regimen compared to patients who received non-GTX regimens (9.45 vs 6.08 months; P-0.0157). GTX also showed non-statistically significant improvement in mOS compared to FFX (9.45 vs 6.08 months; P-0.1436). Compared with FFX, GTX was associated with fewer severe GI (40 vs 45.5%; p – 1.00) and hematologic (20 vs 36.4%; p – 0.40) toxicities. Conclusions: GTX significantly improved mOS and had fewer severe toxicities compared to non-GTX regimens. Limitations include the retrospective and non-randomized nature of the study and the small sample size. However, GTX may be considered an alternative first line regimen in mPAC patients who are unable to tolerate aggressive regimens such as FFX and in whom the need to balance quality of life with efficacy is particularly important.
Combination of everolimus and lu-177 PRRT in treatment of G1-2 neuroendocrine tumors (NET): Phase 1-2 study.
Authors: Aljubran Ali Husain , Alrowaili Mohamed , Raef Hussein , Bazarbashi Shouki , Alzahrani Ahmed M , Almuhaideb Ahmed , Almanea Hadeel , Badran Ahmed ali , Al-Dalee Abdelmuniem , Tuli Mahmoud
Published: January 2019

386

Background: Everolimus and Lutetium-177 PRRT were approved as monotherapy. However, animal model research showed synergistic effect of the combination. The goal of this study is to assess the safety and efficacy of the combination in treatment of unresectable G1-2 NETs of all gastrointestinal, lung and pancreatic origins. Methods: This is a phase 1-2 study. Phase 1 part involves finding the maximum tolerating dose (MTD) of everolimus and accordingly to recommend dose for phase II part. Starting everolimus dose was 5 mg OD. Patients were treated concurrently with Lu-177 DOTATOC therapy at intervals of 8 weeks (+/-1 week) with average of 4 sessions. Sample size calculation was based on the expected response of the combination to be 30% with power of 80 and type 1 of .05, compared to the known response rate of everolimus alone of 5%. Primary end point is safety. Other end points include response rate, PFS and OS. Results: Eleven patients, with progressive disease, were enrolled. Characteristics are summarized in the table. Everolimus MTD was 10 mg once daily. However, dose was reduced to 5 mg OD in 3 patients and to 5 mg once every other day in 2 patients. Median number of sessions of Lu-177: 3 sessions, and median cumulative dose: 300 mci. Most common G1-2 toxicities: stomatitis (90.9%), Nausea (72.7%), Fatigue (63.6%), anorexia (36.4%), diarrhea (36.4%) and skin and nail changes (36.4%). G3 toxicities (36%) were infection, fatigue, pneumonitis and neutropenia. No grade 4 toxicities. Reasons of discontinuation were toxicity in 3 patients, progression in 3, stroke in 1 and due to interruption of therapy in 4 patients. ORR: 1 PD, 1 PR and 9 SD. At median FU of 18.9 months, 7 patients are still alive, 3 died, and 1 lost to FU. Median PFS: 23.3 months. Conclusions: Combination of Everolimus and the Lu-177 PRRT appear to be safe and effective. Four patients, due to strict compliance criteria in the study protocol, were removed from the study prematurely resulting in undertreatment. Larger and randomized studies are required to confirm such findings.[Table: see text]
Understanding practices and gaps in multidisciplinary hepatocellular carcinoma (HCC) care within the community oncology setting.
Authors: Lucas Lorna , Philip Philip Agop , Gandee Marianne , Kramar Amanda
Published: January 2019

390

Background: HCC incidence continues to rise and presents a myriad of complex challenges involving multi disciplines to screen, diagnose, and provide personalized therapy. Recent advances in diagnostics and therapies necessitate a well-coordinated multidisciplinary approach in managing HCC patients, signaling a need to understand care within community care. The study aimed to understand how multidisciplinary cancer programs were structured to manage HCC care and to identify challenges and practices for management of HCC, a cancer less commonly seen in community care settings. Methods: The Association of Community Cancer Centers (ACCC) developed a survey to identify factors associated with delivery and coordination of care for HCC patients. The survey deployed electronically in July 2018 to multidisciplinary providers, representing 17 oncology professions. Of responses (n = 31), 69% identified their care setting as a “non-teaching community hospital, freestanding cancer center, private practice or other.” Results: 61% of respondents indicated their cancer programs do not have specialized hepatobiliary multidisciplinary team. Among those who have hepatobiliary multidisciplinary teams the composition and degree of specialization varied. 85% of respondents that do not have a specialized hepatobiliary team indicated that HCC patients are managed in consultation with a general tumor board. 52% indicated their program discussed participation in clinical trials with all HCC patients, and 55% of cancer programs conducted HCC clinical trials. 52% indicated their program had a formal pathway that outlines adherence to the NCCN guidelines for HCC management, 5% were in the process of developing and 43% were not in the process of developing such a pathway. Of respondents that reported barriers their program faces (n = 13) 31% indicated lack of psychosocial services, lack of screening and no/limited access to clinical trials. 23% responded delayed treatment and 15% responded delayed diagnosis as challenges. Conclusions: Review of multidisciplinary care delivery for HCC patients revealed unique protocols and challenges within primarily community-based settings.
Dose intensity of neoadjuvant FOLFIRINOX (FFX) in borderline and locally advanced pancreatic cancer (LAPC): A comparison to the adjuvant benchmark.
Authors: Murphy Janet E. , Ly Leilana , Wo Jennifer Yon-Li , Ryan David P. , Clark Jeffrey W. , Yeap Beow Y , Drapek Lorraine C. , Blaszkowsky Lawrence Scott , Parikh Aparna Raj , Nipp Ryan David , Kwak Eunice Lee , Allen Jill N. , Corcoran Ryan Bruce , Faris Jason Edward , Zhu Andrew X. , Goyal Lipika , DeLaney Thomas F. , Ferrone Cristina , Fernandez-del Castillo Carlos , Weekes Colin D.
Published: January 2019

392

Background: Optimal timing and duration of FFX for resectable, borderline resectable, and LAPC has not been established. The PRODIGE 24/CCTG PA.6 study used 12 cycles of adjuvant modified FFX (eliminating bolus 5FU, irinotecan at 150mg/m2) demonstrating superior DFS (21.6 mo) over gemcitabine (12.8 mo). However, only 48% of patients (pts) received 70% of intended chemo dosing, and 66.4% of pts completed all doses due to postoperative tolerability. We conducted total neoadjuvant therapy (TNT) studies in borderline and LAPC. (LAPC study included Losartan experimentally.) Dose intensity of TNT with FFX is compared to the benchmark adjuvant data. Methods: In this retrospective analysis, chemotherapy data were analyzed from NCT01821729 (LAPC) and NCT01591733 (Borderline). Both studies included 8 cycles of neoadjuvant FFX: b5FU 400mg/m2, CI 5U 1200mg/m2/d x 2d, oxaliplatin 85mg/m2, and irinotecan 180mg/m2. Results: 92 pts were studied: Borderline n = 43, LAPC n = 49. Sixteen of 92 (17.3%) patients discontinued chemotherapy prior to 8 cycles due to: withdrawal of consent (2), chemotherapy toxicity (6), progression (4), and disease-related complications (4). 82.6% of patients completed 8 doses. 61.4% of all bFU was given at the intended dose of 400 mg/m2. The mean relative dose intensity of b5FU (the actual cumulative dose relative to the planned cumulative dose over 8 cycles) was 72%. 65.5% of patients required a reduction in b5FU over eight cycles. Data for all chemotherapy are presented in Table 1. Overall, 71 of 92 patients (77.2%) had > 70% dose of FFX, with mean relative dose intensity of 81.2%. Among surgically resected patients, mPFS was 21.3 months in LAPC (n = 34) and 48.6 months in Borderline (n = 33). Conclusions: Compared to adjuvant therapy, dose intensity was achieved in a higher proportion of participants with TNT, utilizing a FFX regimen that included b5FU and irinotecan at 180mg/m2. PFS among resected patients reflects this highly active treatment. [Table: see text]
Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.
Authors: Chakrabarti Sakti , Kommalapati Anuhya , Tella Sri Harsha , Huffman Brandon M. , Yadav Siddhartha , Riaz Irbaz Bin , Goyal Gaurav , Borad Mitesh J. , Mahipal Amit
Published: January 2019

393

Background: Clinicopathological features and the outcomes of patients with fibrolamellar hepatocellular carcinoma (FLHCC) are not clearly defined. Methods: Data were collected by retrospective chart review on 42 patients with FLHCC treated between 1990 and 2017 at the Mayo Clinic. Clinicopathological characteristics, response to treatment, recurrence pattern and survival were analyzed. Results: Of 42 patients (17 males and 25 females; median age at diagnosis 22 years, range 15 to 39), 10 patients (23%) had stage I disease and 32 patients (77%) had stage II to IVB disease. All 10 patients with stage I disease and 21 of 32 patients with stage II-IVB disease underwent resection at presentation. In stage I patient group, 6 patients experienced recurrence with a median time to recurrence of 30.5 months, resulting in a 5 year overall survival (OS) of 86%. Patients with stage II to IVB disease who underwent resection (n=21) at presentation had a median OS of 32.5 months and 5 year OS of 44%. In the upfront surgery group, 71% of the patients experienced recurrent disease. The median OS of patients with unresectable disease (n=11) was 10 months. Systemic therapy was given to 17 patients which included sorafenib, FOLFOX (5-fluorouracil/leucovorin and oxaliplatin), gemcitabine plus oxaliplatin, single agent adriamycin or gemcitabine, capecitabine plus interferon alfa, gemcitabine plus cisplatin, cisplatin plus adriamycin and nivolumab . Sorafenib was given to 9 patients and 4 patients achieved stable disease (SD) with duration ranging from 5 months to 5 years. One programmed cell death receptor positive-1 patient had a durable complete response after 2 months of therapy with nivolumab. Conclusions: In FLHCC, surgical resection was associated with prolonged OS. However, recurrences were common after the surgery. Limited benefit was derived from the systemic treatment. In rare cases, therapy with a checkpoint inhibitor may provide a viable treatment option.
A network meta-analysis of adjuvant systemic therapy in resected pancreatic cancer.
Authors: Chaves Porras Jorge , Perry Kaitlyn , Putri Rahmadian Amanda , Delos Santos Seanthel , Ko Yoo-Joung , Berry Scott R. , Doherty Mark , Chan Kelvin K.
Published: January 2019

396

Background: Multiple randomized controlled trials (RCTs) have established several systemic therapy regimens as adjuvant therapy treatment options for resected pancreatic cancer, including modified FOLFRINOX (mFFX), gemcitabine and capecitabine (GemCap) and S1, mostly based on comparison with gemcitabine (Gem) alone. Many of these regimens have not been directly compared in RCTs and their relative survival benefits are unknown. Methods: A systematic review was conducted using MEDLINE, EMBASE, Cochrane Central and ASCO abstracts to identify phase III RCTs up to June 2018 that examined adjuvant systemic therapy in resected pancreatic cancer. Two reviewers independently reviewed the studies and discrepancies were resolved either by discussion or by a third reviewer. Data including study characteristics and outcomes including overall survival (OS) and disease-free survival (DFS) were extracted. Indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analyses (NMA) (R package “netmeta”) which maintains randomization within trials. Results: Nine phase III RCTs involving 3,394 patients and 6 regimens (5-flourouracil and folinic acid, Gem, gemcitabine and erlotinib (GemErl), GemCap, mFFX and S1) were identified. Hazard ratios (HR) and 95% confidence intervals (CI) of OS and DFS of selected comparisons from the results of the NMA are shown in the table. Conclusions: Both mFFX and S1 appeared to be superior to GemCap and can be considered as reasonable standard treatment options for suitable patients and as control arm regimens of future adjuvant clinical trials. [Table: see text]
Predictors of survival in pancreatic squamous cell carcinoma (PSCC): An analysis from the National Cancer Database (NCDB).
Authors: Kommalapati Anuhya , Tella Sri Harsha , Goyal Gaurav , Mahipal Amit
Published: January 2019

399

Background: PSCC is a rare form of exocrine pancreatic malignancy with a dismal prognosis. Using the NCDB, we determined the prognostic factors and survival outcomes of PSCC in the United States. Methods: We performed a retrospective analysis of patients with histologically confirmed PSCC from 2004-2015 using NCDB. Kaplan-Meier method and log-rank test were used to perform overall survival (OS) analysis. Hazard Ratios were calculated using the Cox-proportional hazard method. Results: Of the 654 cases included in our analysis, 46% were female. Median age at diagnosis was 70 years and did not differ by sex (p = 0.19). The proportion of patients with stage I, II, III and IV diseases were 5%, 18%, 12%, and 54%, respectively (10%, unknown stage). Among these, 23% (35 of 150) of stage I and II disease, 10% (8 of 78) of stage III, and 2% (7 of 353) received surgical resection of the primary tumor. The rate of R0 resection was 74% in stage I and II; 38% in stage III; 29% in stage IV disease. Median OS for the entire cohort was 4 months and was significantly higher in patients who received surgical resection of the primary tumor (17 vs. 4 months, p < 0.001). On stage wise sub-group analysis, stage I-II patients had OS benefit from surgery (21 vs. 5 months, p < 0.001) as opposed to stage III (7 vs. 6 months, p = 0.31) and IV disease (5 vs. 3 months, p = 0.17). Adjuvant chemotherapy had no role in prolonging survival in stage I-II disease (20 vs 24 months, p = 0.6). Stage IV patients treated with chemotherapy had a better median OS than those without (5 vs. 2 months, p < 0.0001). On Cox multivariable analysis, stage IV disease (HR: 1.92 CI: 1.46-2.52, p < 0.001) and advanced patient age (HR: 1.02; CI:1.01-1.03, p < 0.001 were associated with poor OS, whereas OS was not dependent on the sex, race, grade, insurance status, surgery, and chemotherapy. Conclusions: This is the largest registry-based study on PSCC to date. PSCC had a diverse OS varied significantly according to increasing age and stage of the disease at presentation. Surgical resection of primary tumor was associated with improved OS in stages I-II, whereas chemotherapy improved OS in stage IV disease. The results of our study may aid the prognostication of patients and in treatment decision making.
A phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of andecaliximab combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma (GAMMA-1).
Authors: Shah Manish A. , Yanez Ruiz Eduardo Patricio , Bodoky Gyorgy , Starodub Alexander , Cunningham David , Yip Desmond , Wainberg Zev A. , Bendell Johanna C. , Thai Dung , Bhargava Pankaj , Ajani Jaffer A.
Published: January 2019

4

Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. A phase I/Ib study of mFOLFOX6 + ADX revealed encouraging antitumor activity in patients (pts) with gastric or gastroesophageal junction (GEJ) adenocarcinoma (median first-line, progression-free survival [PFS] of 9.9 months). Methods: This phase 3, randomized, double-blind, multicenter study investigated the efficacy and safety of mFOLFOX6 with/without ADX in pts with untreated HER2-negative gastric or GEJ adenocarcinoma. Randomization was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + placebo (PBO). Oxaliplatin was administered on Days 1 and 15 of each 28-day treatment cycle (total of 6 cycles), followed by leucovorin and 5-fluorouracil dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. ADX/PBO 800 mg was infused on Days 1 and 15 of each 28-day cycle until disease progression. The study had 85% power (one-sided significance of 0.025) to detect a hazard ratio of 0.7 for overall survival (OS) by intention-to-treat analysis using the log-rank test. Secondary endpoints were PFS, objective response rate (ORR, RECIST 1.1), and safety. Results: Between September 2015 and May 2017, 432 pts were randomized; 218 pts to ADX and 214 pts to PBO. Median (95% CI) OS was 12.5 (11.2, 14.0) vs 11.8 (10.3, 13.5) months in the ADX and PBO groups, respectively (HR 0.93 [0.74, 1.18], two-sided p=0.56). Median PFS was 7.5 vs 7.1 months in the ADX and PBO groups, respectively (HR 0.84 [0.672, 1.038], two-sided p=0.10). Median investigator assessed ORR was 50.5% vs 41.1% in the ADX and PBO groups, respectively (two-sided p=0.049). The most common treatment-emergent adverse events were nausea, diarrhea, neutropenia, and fatigue. There were no meaningful differences in the safety profile of the ADX vs PBO groups. Subgroup analysis is ongoing. Conclusion: Additionof ADX to mFOLFOX6 does not improve OS in pts with untreated HER2-negative gastric or GEJ adenocarcinoma. Clinical trial information: NCT02545504.
Oral chemotherapy as second-line treatment option for gemcitabine-refractory advanced pancreatic cancer with poor performance status.
Authors: Park Se Jun , Lee Myung Ah
Published: January 2019

405

Background: There is few data for effective second-line treatment in advanced pancreatic cancer, and most patients have poor performance status after progressive disease. We evaluated the efficacy, toxicity, and median dose intensity of oral chemotherapy, capecitabine, or TS-1 in gemcitabine-refractory advanced pancreatic cancer for second-line treatment. Methods: Patients who have progressive disease after first-line gemcitabine-based chemotherapy were retrospectively analyzed between Jan. 2011 and Nov. 2017. These patients were treated with capecitabine or TS-1 as second-line treatment. Capecitabine were administered as 2,500 mg/m2 divided dose on day 1-14, followed by one week rest. In TS-1 group, TS-1 was taken orally based on patient’s BSA (60mg twice daily in BSA > 1.5, 50mg twice daily in BSA 1.25-1.5, and 40mg twice daily in BSA < 1.25) through 28 days, by two week rest. Median dose intensity was compared by calculating a percent of target dose achieved in the average cycle for each patient. Results: Of the total 62 patients, 41 patients were treated with capecitabine and 21 patients were treated with TS-1. The median age was 61 years for the capecitabine group compared with 62 years for the TS-1 group. In capecitabine group, males were 56%, and in TS-1 group, males were 66%. 29% of capecitabine group received prior fluorouracil base therapy, and 47% of TS-1 group were receiving such therapy. The objective response rate was similar in the two groups: 12.2% with capecitabine and 4.8% with TS-1 (p = 0.358). There was no difference in median progression free survival between capecitabine and TS-1 (2.1 months vs. 2.7 months, p = 0.102), however, TS-1 group showed better median overall survival time than capecitabine group (6.9 months vs. 4.6 months, p = 0.048). Most of the adverse events were similar in both group, except that grade 3 or 4 mucositis was more common in TS-1 group. There was no significant difference in median dose intensity between two groups. (Capecitabine 91.5% vs. TS-1 90.1%, p = 0.216). Conclusions: Oral agents such as TS-1 or capecitabine can be second-line treatment for advanced pancreatic cancer patients with poor performance status after progression to gemcitabine-based regimen.
Multi-agent neoadjuvant chemotherapy improves response and survival in patients with resectable pancreatic cancer.
Authors: Maramara Taylor , Huston Jamie , Shridhar Ravi , Meredith Kenneth L
Published: January 2019

409

Background: Neoadjuvant therapy (NT) for resectable pancreatic adenocarcinoma (PAC) continues to be debated. We sought to establish the impact of single agent (SAC) versus multi-agent chemotherapy (MAC) with or without radiation (RT) on survival in patients with resectable pancreatic cancer. Methods: Utilizing the National Cancer Database we identified patients with PAC who underwent up front surgery (UFS), SAC, or MAC ± RT followed by surgery. Patient characteristics and survival were compared with Mann-Whitney U, Pearson’s Chi-square, and the Kaplan-Meier method. Multivariable analysis (MVA) was developed to identify predictors of survival. All tests were two-sided and α < 0.05 was significant. Results: We identified 26,563 patients of which, 23,877 (89.9%) UFS, 1,482 (5.6%) NT+RT (SAC+RT 768, MAC+RT 560), and 1,204 (4.5%) chemo only (SAC 262, MAC 864) with a median age of 66 (25-90). The median tumor size was smaller, p = 0.003 and Charlson/Deyo was lower, p = 0.008 in the UFS. Despite this, the 90 day mortality was higher at 8% versus 7.5% in NT+RT and 4.8% in NT, p = 0.003. There were higher R0 resections in the NT+RT versus NT-RT or UFS, 82.4%, 80.5%, and 76%, p < 0.001. Additionally, there were less N1 disease in NT+RT 35.4%, 59.5%, and 68.1%, p < 0.001. Pathologic complete response (pCR) rates were higher in the NT+RT versus NT-RT, 3.1% versus 1.7%, p < 0.001. Examining the response rates by SAC±RT and MAC±RT, pCR was 0.5% in SAC, 2.8% SAC+RT, 2.2% MAC, and 3.3 MAC+RT, p = 0.004. The median survival was 22.2 mo in UFS, 23.1 mo in SAC, 26 mo in SAC+RT, 27.9 mo in MAC+RT, and 29.8 mo in MAC, p < 0.001. On multivariable analysis, age, Chalson/Deyo score, tumor size, grade, margin status, facility volume, and MAC were predictors of survival. Conclusions: Multi-agent chemotherapy with or without radiation improves overall survival, R0 resections rates, and complete pathological response rates in patients undergoing neoadjuvant therapy for resectable pancreatic cancer.
Neutrophil/lymphocyte ratio (NLR) may predict prognostic factor with gemcitabine, cisplatin (GC) for patients with advanced biliary tract cancer.
Authors: Otsuru Toru , Sakai Daisuke , Kimura Akie , Inagaki Chiaki , Nishida Naohiro , Iwagami Yoshifumi , Noda Takehiro , Asaoka Tadafumi , Gotoh Kunihito , Kobayashi Shogo , Eguchi Hidetoshi , Satoh Taroh
Published: January 2019

410

Background: There is little information available about prognostic markers of GC (gemcitabine, cisplatin) in patients with advanced biliary tract cancer (BTC). Neutrophil/lymphocyte ratio (NLR) in several cancers was might to be a prognostic factor associated with clinical outcomes, we examine NLR in patient with BTC underwent chemotherapy (GC). Methods: Retrospective chart review for consecutive patients who underwent GC for advanced BTC in our institute were performed. The patients who were enrolled in ongoing clinical trials were excluded. Gemcitabine and cisplatin were administered intravenously at doses of 1,000 or 25 mg/m2, on day one and eight, every three weeks. We divided these patients based on estimated NLR, and evaluated the clinicopathological factors and survival in the two groups (NLR ≥ 3 or < 3). Results: 57 patients from 2013 to 2017 were reviewed. 23 patients were in NLR ≥ 3 group and 34 patients were in NLR < 3 group. Patients characteristics were as follows; median age, 68 years old (range: 38-83) years: male 36 (63%); primary tumor lesion, intrahepatic bile duct 6 (10%)/extrahepatic bile duct 32 (56%)/gallbladder 18 (32%)/ampulla of vater 1 (2%); therapeutic purpose, palliative 50 (88%)/adjuvant 5 (8%)/neoadjuvant 2 (4%); PS, 0/1. Response rate of the patients who had measurable lesion according to RECIST v1.1 was 17% (8/46), and disease control rate was 70% (32/46). The progression-free survival rate between the two groups is not significantly different. Although, the median overall survival (OS) of NLR ≥ 3 group was 11.8 months, while OS of NLR < 3 group was 29.2 months. The overall survival rate in the NLR ≥ 3 group was significantly lower than that in the NLR < 3 group ( P = 0.0339). Conclusions: Our study confirmed that high NLR is associated with worse OS and PFS, and suggested it may be a predictive marker for GC chemotherapy in patients with BTC.
Pulsed high-dose erlotinib with gemcitabine as second-line therapy for pancreatic adenocarcinoma.
Authors: Larson Christopher , Reid Tony R.
Published: January 2019

421

Background: The options for treatment of pancreatic cancer follow progression on first line therapy are limited and associated with significant toxicity. Erlotinib has been approved for treatment of pancreatic cancer in first-line therapy. We conducted a phase I dose-escalation trial of erlotinib in combination with gemcitabine for patients that had failed first-line therapy. Erlotinib was administered by a novel pulse-dose schedule where the drug was given orally for 3 days every two weeks. Purpose: Assess the safety and determine a recommended phase II dose for pulsed high dose erlotinib in combination with gemcitabine for pancreatic cancer, and obtain preliminary data on activity. Methods: Patients with pancreatic cancer that progressed on or after first-line therapy were treated in a dose escalation study with erlotinib at 750 to 2,000 mg daily for three days every two weeks in combination with weekly gemcitabine at 1,000 mg/m2 for three weeks on and one week off. Results: No dose limiting toxicities were encountered and erlotinib-induced rash was mild and transient. Median overall survival was 6.7 months and 12-month overall survival was 27%. Progression free survival but not overall survival was longer in patients who did not previously receive gemcitabine. Rash was not associated with longer survival. Conclusions: The recommended phase II dose is erlotinib 2,000 mg daily for three consecutive days every two weeks in combination with gemcitabine. Tolerability was excellent, and outcomes were better than expected for second-line therapy in pancreatic cancer. Further studies are warranted, both as therapy after first-line and as first-line therapy for patients unable to tolerate more aggressive regimens. Clinical trial information: NCT02154737.
Real world eligibility for cabozantinib (C), regorafenib (Reg), and ramucirumab (Ram) in hepatocellular carcinoma (HCC) patients after sorafenib (S).
Authors: Fung Andrea S. , Tam Vincent C. , Meyers Daniel E. , Sim Hao-Wen , Knox Jennifer J. , Zaborska Valeriya O. , Davies Janine Marie , Ko Yoo-Joung , Batuyong Eugene , Cheung Winson Y. , Samawi Haider , Lee-Ying Richard M.
Published: January 2019

422

Background: The CELESTIAL, RESORCE, and REACH-2 trials showed survival benefit of C, Reg, and Ram, respectively, when given after S to HCC patients. However, strict eligibility criteria (SEC) may limit generalizability. In clinical practice, modified eligibility criteria (MEC) may be used to offer treatments to select patients with slightly worse performance status (ECOG 2) or limited liver dysfunction (Child-Pugh (CP) B7). This study evaluated which patients in the real world would be eligible for these new treatments using SEC and MEC, and their prognostic impact. Methods: HCC patients who received S between 01/2008-06/2017 in British Columbia, Alberta, Princess Margaret Cancer Centre, and Sunnybrook Cancer Centre in Canada were included. Clinical, pathologic, laboratory and outcome data were collected. Patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, REACH-2 clinical trial SEC or MEC. Median overall survival (mOS) for these groups was assessed using the Kaplan-Meier method. Results: A total of 730 patients were identified. Using SEC, only 13.1% of patients would be eligible for C, Reg, or Ram (table). Expanding eligibility to include patients who meet MEC increased the proportion of eligible patients to 31.7%. Patients who met SEC had longer mOS compared to those who were ineligible. The most common reasons for not meeting SEC across all 3 trials were ECOG ≥ 2 (61.7%) and CP ≥ B (63.9%). Higher ineligibility for Reg or Ram was likely driven by strict trial-specific criteria, with 28.0% of patients ineligible for Reg due to S intolerance and 58.9% ineligible for Ram due to AFP < 400. Conclusions: Only a small proportion of real-world HCC patients would be eligible for C, Reg, or Ram based on SEC. More than twice as many patients would likely receive treatment if MEC were applied. If MEC are adopted, ongoing real-world evidence generation will be important to evaluate outcomes in these unstudied patient groups. [Table: see text]
Regional, racial/ethnic, and socioeconomic disparities and treatment outcomes in patients with hepatocellular carcinoma (HCC) in the United States.
Authors: Parikh Neehar , Malahias Laura , Brown Robert S , Cabrera Roniel , Jones Patricia Denise , Landis Charles , Lee Hannah , Mantry Parvez , Mena Edward , Poddar Nishant , Reddy K. Rajender , Shrestha Roshan , Thuluvath Paul , Zink Richard , Singal Amit G.
Published: January 2019

424

Background: Racial/ethnic (R/E) minorities and patients of low socioeconomic (SE) status are reported to have higher mortality related to HCC than their counterparts. However, prior studies are limited to administrative datasets without annotation for clinical covariates or represent single-center data with limited generalizability. The aim of this analysis was to characterize geographic, R/E, and SE disparities in HCC presentation, treatment, and survival among a representative sample of HCC patients in the US. Methods: TARGET-HCC is an observational, retrospective/prospective study of patients with HCC from academic and community sites. Complete medical records from consented patients are abstracted into a secure database. Multivariable logistic regression with random intercepts for site and Cox proportional hazard models with frailty adjustment were fit with adjustment for age, sex, BMI, liver disease etiology (LDE) and history of alcohol abuse to identify factors associated with early HCC detection, receipt of curative-intent therapy (CIT) and overall survival. Results: 925 patients with HCC (63% non-Hispanic white, 21% black, and 8% Hispanic) were consented from 42 sites in the US (22% Northeast, 27% Southeast, 21% Midwest, 14% South, and 16% West). Median age was 64 years and 76% were men. The most common LDE was hepatitis C (72%), and 72% had Child Pugh A cirrhosis. Most patients were diagnosed with early-stage HCC (72% Barcelona Clinic Liver Cancer 0/A). CIT was the initial therapy in 249 (32%), including 32% of BCLC 0/A. Although early tumor detection and CIT did not differ by region or R/E, there were SE disparities in CIT. Among those with early stage HCC, patients with private insurance [OR = 0.51, 95% CI (0.29, 0.91)] or Medicaid [OR = 0.50, 95% CI (0.25, 0.97)] were significantly less likely to undergo CIT. Overall survival was associated with BCLC stage and type of HCC treatment, with no significant association with region, R/E, or insurance. Conclusions: In this sample of HCC patients, there were no geographic or R/E disparities in early detection, treatment, and survival although SE disparities in administration of CIT were identified and warrant further study.