bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of SM-88 in PC after multiple prior lines and ECOG < 2.
Authors: Noel Marcus Smith , Wang-Gillam Andrea , Ocean Allyson J. , Del Priore Giuseppe , Picozzi Vincent J.
Published: January 2019

310

Background: Advanced PC patients with ≥ 3Ls of chemo or ECOG PS 2 are generally excluded from clinical trials. SM88 demonstrated no drug related AEs > grade 2 in an interim prostate phase 2 (JCO 2018 36:6S P 175). We sought to determine the feasibility of a trial in this vulnerable population using SM88. Methods: Prospective randomized phase 2 of SM-88 (tyrosine derivative, CYP3a4 inducer, mTOR and oxidative stress catalyst) in patients with locally PD or mPC, ECOG PS < 2 and ≥ 2 weeks from prior therapy. Results: Mean age = 64.9 (range 45.6-84.1); 45.5% female, 93.1% white, 6.9% other; median prior lines = 3 (range 1-6); 12% had prior RT and 17% surgery. Median ECOG PS was 1 with 36.6% 0, 63.3% 1 and 0% ECOG PS 2. From April 2018 to this abstract deadline, 72 patients at 24 sites have consented; 36 patients initiated therapy, 19 failed screening and 17 remained in screening. Time from opening trial to first patient consented = 5.1 wks; median time last regimen to consent = 6.7 wks; from consent to drug administration (C1D1) = 1.7 wks. Subjects traveled up to 2600 miles to enroll at a site with an open slot. Median number of subjects/site = 3 (1-15). Median time on trial is 52 days (1-22 wks). There were 15 unrelated SAEs among 36 randomized subjects; three subjects died after consenting but before receiving study drug (table). Grade 4 and 5 SAEs∗ were more common before receiving drug or unrelated to drug (26/94) than at least possibly drug related (0/17) (Fisher p < 0.05). Efficacy using RECIST, PERCIST and BICR along with CTCs, 19.9, NLR, PROs and other outcomes are being collected with high compliance. Conclusions: This prospective SM88 trial suggests that heavily pretreated PC patients with criteria that includes less than ideal ECOG can participate and gain access to novel therapies. This trial plans to enroll 99 additional subjects in under a year. Although ECOG 2 was allowed none have been consented to date and may reflect investigator bias on enrollment or PS assessment. Investigators can meet the needs of this patient population by considering them for inclusion in future drug development trials. Clinical trial information: NCT03512756. [Table: see text]
Predictive role of temporal changes in intratumoral metabolic heterogeneity during palliative chemotherapy in advanced pancreatic cancer patients: A prospective cohort study.
Authors: Yoo Shin Hye , Kang Seo Young , Cheon Gi Jeong , Oh Do-Youn , Bang Yung-Jue
Published: January 2019

311

Background: Metabolic intratumoral heterogeneity (ITH) is known to be related with cancer treatment outcome. However, information on the temporal changes in metabolic ITH during chemotherapy and the correlations between metabolic changes and treatment outcomes in patients with pancreatic cancer (PC) is sparse. We aimed to analyze the temporal changes in metabolic ITH and the predictive role of its changes in advanced PC patients who underwent palliative chemotherapy. Methods: We prospectively enrolled unresectable locally advanced or metastatic PC patients before initiation of first-line palliative chemotherapy. 18F-fluorodeoxyglucose positron emission tomography was performed at baseline (T1) and at the first response follow-up (T2). Standardized uptake values (SUVs), volumetric parameters, and textural features of the primary pancreatic tumor were analyzed. Relationships between the parameters at T1, T2, and changes in the parameters with response to therapy, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Among 63 enrolled patients, the best objective response rate was 25.8% (95% confidence interval [CI], 14.6% to 37.0%). Sixteen (25.8%) patients who obtained partial response were classified as responders and 46 (74.2%) as nonresponders. The median PFS and OS were 7.1 months (95% CI, 5.1 to 9.7 months) and 10.1 months (95% CI, 8.6 to 12.7 months), respectively. Most of the parameters changed significantly during the first-line chemotherapy, in a way of reducing ITH. Metabolic ITH was more profoundly reduced in responders than in nonresponders. Multiple Cox regression analysis identified high baseline compacity ( P = 0.023) and smaller decreases in SUVpeak ( P = 0.007) and entropyGLCM ( P = 0.033) to be independently associated with poor PFS. Patients with a high CA 19-9 ( P = 0.042), high pretreatment SUVpeak ( P = 0.008), and high coefficient of variance at T2 ( P = 0.04) showed worse OS. Conclusions: Reduction in metabolic ITH during palliative chemotherapy in advanced PC patients is associated with response to therapy and might be predictive of PFS and OS.
Neoadjuvant chemotherapy followed by surgery versus upfront surgery in patients with borderline resectable and locally advanced unresectable pancreatic adenocarcinoma.
Authors: Kang Junho , Yoo Changhoon , Shin Sang Hyun , Kim Kyu-Pyo , Jeong Jae Ho , Chang Heung-Moon , Lee Sang Soo , Park Do Hyun , Song Tae Jun , Seo Dong Wan , Lee Sung Koo , Kim Myung-Hwan , Park Jin-hong , Hwang Dae Wook , Song Ki Byung , Lee Jae Hoon , Ryoo Baek-Yeol , Kim Song Cheol
Published: January 2019

312

Background: Although neoadjuvant chemotherapy (NACT) has been widely investigated, the magnitude of the clinical benefit and the potential risk of NACT followed by surgery compared with upfront surgery remains unclear for patients with locally advanced pancreatic cancer (LAPC). Methods: This retrospective, prospective cohort-based analysis included 135 patients who underwent NACT followed by surgery and 359 patients who received upfront surgery for LAPC between October 2005 and April 2017. Disease-free survival (DFS) and overall survival (OS) from surgery were compared between the two groups. Results: There were no significant differences in gender (male, 53% vs 56%) and age (median 60 vs 61 years) between the NACT followed by surgery group and upfront surgery group. As NACT, gemcitabine-based regimens and FOLFIRINOX were used in 69 (51%) and 66 (49%) patients, respectively. The NACT followed by surgery group showed significantly less advanced T stage (T3–4, 93% vs 99%, p = 0.001) and N stage (N+, 49% vs 71%, p < 0.001) than the upfront surgery group. NACT followed by surgery was significantly associated with better OS (median, 25.4 [18.6–32.2] vs 17.1 [15.5–18.7] months, p = 0.001) and DFS (median, 9.0 [95% CI, 6.8–11.2] vs 7.1 [6.4–7.8] months, p = 0.005) than upfront surgery. These results were consistent in the multivariate analysis for OS (adjusted hazard ratio [aHR], 0.73 [95% CI, 0.56–0.96], p = 0.02) and DFS (aHR, 0.72 [95% CI, 0.56–0.93], p = 0.01). There was no difference in length of hospital stay (median 13 vs 17 days, p = 0.14) for surgery between the two groups, and the NACT followed by surgery group showed a significantly lower incidence of postoperative complication than the upfront surgery group (38% vs 27%, p = 0.03). Conclusions: The present study revealed that NACT followed by surgery may provide survival benefit compared with upfront surgery in LAPC without causing significant safety issues.
Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety in Japanese patients across two global randomized phase III studies (REACH-2 and REACH).
Authors: Kudo Masatoshi , Okusaka Takuji , Motomura Kenta , Ohno Izumi , Morimoto Manabu , Seo Satoru , Wada Yoshiyuki , Sato Shinpei , Yamashita Tatsuya , Furukawa Masayuki , Aramaki Takeshi , Nadano Seijin , Ohkawa Kazuyoshi , Fujii Hirofumi , Kudo Toshihiro , Furuse Junji , Takai Hiroki , Homma Gosuke , Yoshikawa Reigetsu , Zhu Andrew X.
Published: January 2019

320

Background: Ramucirumab (RAM), a human IgG1 monoclonal antibody, inhibits ligand activation of VEGFR2. REACH and REACH-2 were two global, randomized, double-blind, placebo (PBO)-controlled multicenter, phase III studies of RAM versus PBO in patients with HCC after prior sorafenib. REACH-2 confirmed RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. Methods: Other than AFP levels, study designs and eligibility for both studies were similar. All patients received RAM (8 mg/kg) I.V. or PBO every 14 days. Pooled analyses were performed to further support the assessments of efficacy and safety in Japanese patients with baseline AFP ≥ 400 ng/mL. Results: In total, 101 Japanese patients were pooled from REACH and REACH-2 (n = 61 RAM; n = 40 PBO). Pooled baseline patient characteristics were balanced between arms including baseline AFP and etiology. As in the individual studies, improvement in OS (median OS 10.78 vs 4.47 mo; HR 0.555; 95% CI 0.348, 0.885; p = .0124) was observed. Improvements in PFS (median PFS 3.88 vs 1.41 mo; HR 0.341; 95% CI 0.212, 0.550; p < .0001), ORR (9.8% vs 2.5%, p = .1285), and disease control rate (67.2% vs 35.0%, p = .0035) were also observed. Consistent with individual study results, hypertension was the only grade 3 or higher adverse events of special interest among ≥ 5% patients that was more frequently observed in the RAM arm (13.1%) compared with the PBO arm (5.0%). Conclusions: Pooled analysis of two phase III trials of RAM as second-line treatment in patients with HCC following first-line sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Japanese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the Japanese subpopulation were consistent with the entire population (median OS 8.1 vs 5.0 mo; HR 0.694; p = .0002. Zhu AX et al., World GI 2018). Further analysis to characterize the Japanese patients compared to the non-Japanese population is planned. Clinical trial information: NCT01140347 (REACH), NCT02435433 (REACH-2).
The role of perioperative systemic therapy in localized pancreatic neuroendocrine tumor.
Authors: Xie Hao , Yadav Siddhartha , Keutgen Xavier , Hobday Timothy J. , Strosberg Jonathan R. , Halfdanarson Thorvardur Ragnar
Published: January 2019

322

Background: The role of perioperative systemic therapy (PST) is unclear in the management of localized pancreatic neuroendocrine tumor (pNET). We aim to evaluate the benefit of PST compared to surgical resection alone in localized pNET. Methods: We identified patients with stage I–III pNET who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who underwent PST and surgical resection were matched with patients who received surgery alone by propensity score at 1:1 ratio with nearest neighbor method. Factors predicting the use of PST were identified from logistic regression. Survival was estimated with Kaplan-Meier method and compared with Cox proportional hazards regression. Results: 4919 patients were included in this study with median age of 60 years. 1397 (28%) patients had pNET at the head of pancreas. 2708 (55%) patients had pNET at pancreas body and tail. 334 (6.8%) patients received PST. Factors associated with significant more use of PST compared to surgery alone were age < 65 years, low income, community medical facilities, grade 3/4 tumor, tumor at the head of pancreas, T3-4 tumor and N1 tumor. 310 patients in PST group were matched with 310 patients in surgery alone group, with no significant difference for all covariates after match. For those in PST group, 64 (21%) patients received neoadjuvant systemic therapy, 173 (56%) patients received adjuvant systemic therapy, 7 (2.3%) patients received both, and 66 (21%) patients received PST without clear sequence. In the matched cohort, PST group had significantly shorter overall survival (OS) compared to surgery alone group (median OS 91.1 months versus not reached, p = 0.04). This finding was confirmed by multivariable Cox proportional hazards regression in unmatched cohort with HR 1.5 (95% CI 1.2 – 1.9, p = 0.002). Subgroup analysis in patients with grade 3/4 tumor demonstrated PST group has a trend of shorter OS compared to surgery alone group (median OS 34.1 versus 54.4 months, p = 0.1). Conclusions: PST compared to surgery alone is associated with worse OS in patients with localized pNET. This finding suggests that we may use PST in localized pNET with caution in the absence of solid clinical trial data.
Sorafenib versus hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma: A Japanese multi-center large cohort study.
Authors: Ogasawara Sadahisa , Ueshima Kazuomi , Ikeda Masafumi , Yasui Yutaka , Terashima Takeshi , Yamashita Tatsuya , Obi Shuntaro , Sato Shinpei , Aikata Hiroshi , Ohmura Takumi , Kuroda Hidekatsu , Ohki Takamasa , Nagashima Kengo , Kurosaki Masayuki , Chayama Kazuaki , Kaneko Shuichi , Izumi Namiki , Kato Naoya , Kudo Masatoshi , Omata Masao
Published: January 2019

323

Background: Sorafenib, approved in Japan in 2009, is the first systemic therapy demonstrated to significantly improve overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). In Japan, hepatic arterial infusion chemotherapy (HAIC), which directly delivers high concentrations of cytotoxic agents to liver tumors, has been offered to patients with advanced HCC since before sorafenib was approved. HAIC is particularly used in patients without extrahepatic metastases (EHM). This study aimed to compare the outcomes of patients with advanced HCC who received HAIC and sorafenib. Methods: Consecutive patients with advanced HCC who received sorafenib or HAIC as the first-line systemic therapy were enrolled from 10 Japanese centers. The statistical analysis plan included pre-defined propensity score matching method and risk factors. All statistical analyses were performed by an independent biostatistician. Results: Between June 2009 and May 2016, 2006 patients were enrolled (sorafenib: 1465 patients, HAIC: 541 patients). The mean OS of patients with macrovascular invasion (MVI) and without EHM was significant longer in the HAIC group compared with the sorafenib group. After propensity score matching, there were 172 patients in each cohort. The OS was 9.1 months for the sorafenib group and 10.1 months for the HAIC group (hazard ratio [HR]: 0.668 [95% CI: 0.475–0.935], P = 0.018). There was no significant difference in OS between patients without both MVI and EHM. After propensity score matching, there were 76 patients in each cohort. The OS was 15.4 months for the sorafenib group and 12.2 months for the HAIC group (hazard ratio [HR]: 1.227 [95% CI: 0.699–2.155], P = 0.475). Conclusions: HAIC might be a potential initial treatment for patients with advanced HCC with MVI (without EHM). Currently, several new drugs appear clinically beneficial for patients with advanced HCC. Although this study only focused on sorafenib as the chemo-agent, additional studies should be conducted to confirm the benefits associated with HAIC in a limited population of patients with advanced HCC.
Results from phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer.
Authors: Hashimoto Yusuke , Ueno Makoto , Tanaka Maki , Ikeda Masafumi
Published: January 2019

325

Background: Canerpaturev (C-REV, formerly HF10) is an oncolytic, spontaneous mutant Herpes Simplex Virus type 1, and is one of immunotherapies that combine direct tumor cell killing with immune modulation. The purpose of this study is to determine the recommended dose of C-REV in combination with chemotherapy (Gemcitabine + Nab-paclitaxel; G-nP) in Japanese patients with stage III or IV unresectable pancreatic cancer. We report the safety and antitumor activity data of this study. Methods: This study was a “3 + 3” design with a 2-dose escalation scheme evaluating 2 doses of C-REV. The subjects received C-REV at 1x106 or 1x107 TCID50/mL (up to 2mL, depending on tumor size) intratumorally by EUS-guidance at a 2-week interval in addition to 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel by intravenous infusion on days 1, 8, and 15 of a 4-week cycle. The study treatment could continue up to 1 year if eligible for injection. The primary endpoint was Dose Limiting Toxicity (DLT); the secondary endpoints were adverse events (AEs) assessed per NCI CTCAE v4.0, Best Overall Response Rate (BORR) at 16-week by RECIST and progression-free survival. Results: Six patients (pts) were enrolled and treated: 33% (2/6) men, age range 63 to 72 yrs, disease stage 33% III, 66% IV. Of 6 safety evaluable pts, no DLTs were reported. 16% (1/6) pt(s) had C-REV-related ≥ G3 AE, and it was acute pancreatitis (G3). G-nP-related ≥ G3 AEs observed in more than 2 pts were neutropenia (50%), and the majority of ≥ G3 AEs were similar as the AEs previously reported in G-nP therapy. As of 01 Sep 2018, of the 6 efficacy evaluable pts, BORR at 16-week was 66% (4 PR). Disease control rate was 100% (2 SD), and 1 of 2 SD pts continues the study treatment. We will present the updated data. Conclusions: The recommended dose was determined as 1x107 TCID50/mL. The combination of C-REV and the standard chemotherapy demonstrated a favorable benefit/risk profile and encouraging antitumor activity in Japanese patients with unresectable pancreatic cancer. Clinical trial information: NCT03252808.
Adjuvant chemotherapy with or without sequential radiation in resected pancreatic adenocarcinoma: Who will win RTOG 0848?
Authors: Shinde Ashwin , Li Richard , Glaser Scott , Raoof Mustafa , Chung Vincent , Singh Gagandeep , Warner Susanne , Chen Yi-Jen , Amini Arya
Published: January 2019

334

Background: The current role of adjuvant radiation in the management of resected pancreatic adenocarcinoma (PC) is controversial. A prospective trial, RTOG 0848, is currently in process to determine optimal adjuvant therapy, comparing adjuvant chemotherapy (CT) with or without radiation (RT). We determined outcomes in this population using the National Cancer Database (NCDB). Methods: Patients with non-metastatic PC diagnosed from 2004 to 2015 were identified from the NCDB. Patients who underwent surgery and adjuvant chemotherapy were included. Patients who received RT were only included if RT began at least 4 months after CT, to emulate RTOG 0848 schema. A 6 month landmark analysis was performed. Overall survival (OS) was compared using log-rank Kaplan-Meier for univariate analysis (UVA), and Cox proportional hazards for multivariate analysis (MVA). Logistic regression was used to determine predictors of RT utilization and generate propensity scores. Results: We identified 16075 patients. Median follow-up was 30 months, 37 months for survivors. Patients received sequential RT in 9.5% of cases. On UVA, sequential RT demonstrated OS benefit compared to adjuvant chemotherapy alone (3-year OS 44.6% vs 35.3%, p < 0.001). RT utilization was more likely with diagnosis after 2010, age ≤ 65 years, private insurance, higher income, ≤ 10 miles to treatment facility, treatment in the northeast, node positive disease, positive margins, and head of pancreas primary. On MVA, benefit to RT on OS was maintained (HR 0.68, 95% CI 0.63-0.73, p < 0.001). Other factors that improved OS included diagnosis after 2010, no comorbidity, non-government insurance, higher income, and treatment at academic facility. Factors that predicted for worse OS included increasing pathologic tumor and nodal staging, positive margins, and CA 19-9 above a cut-off of 90. After propensity-adjustment, OS benefit was maintained for RT (HR 0.68, p < 0.001). Conclusions: In a large national database analysis, sequential RT improves survival in patients who receive at least 4 months of adjuvant chemotherapy following upfront resection for pancreatic adenocarcinoma. The results of RTOG 0848 are awaited to confirm these findings.
Combined immune checkpoint inhibition (ICI) with tremelimumab and durvalumab in patients with advanced hepatocellular carcinoma (HCC) or biliary tract carcinomas (BTC).
Authors: Floudas Charalampos S. , Xie Changqing , Brar Gagandeep , Morelli Maria Pia , Fioravanti Suzanne , Walker Melissa , Mabry-Hrones Donna , Wood Brad J. , Levy Elliot B , Krishnasamy Venkatesh P , Greten Tim F.
Published: January 2019

336

Background: Prognosis in advanced HCC and BTC is unfavorable, and 5-year overall survival (OS) rate is less than 20% and 10%, respectively. Single agent ICI in HCC has response rates (RR) of 20%, while early data in BTC reported 17.4% RR. Dual ICI has increased RR in other malignancies. The purpose of this study was to explore the efficacy of the combination of anti-CTLA4 (tremelimumab) with anti-PD-L1 (durvalumab) in advanced HCC and BTC. Methods: Eligible patients with advanced HCC or BTC who had received (or refused) at least one prior therapy, received monthly tremelimumab 75 mg in combination with durvalumab 1500 mg for 4 doses followed by monthly durvalumab 1500 mg monotherapy until progression of disease or unacceptable toxicity. Response was assessed with CT scan every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint is 6-month progression free survival (PFS). Results: Twenty-two patients were enrolled, 10 with advanced HCC and 12 with advanced BTC. Male to female ratio was 14:8, with median age of 62.5 years (range 19-80). Grade 3/4 treatment-related AEs included lymphocytopenia, hyponatremia, bullous dermatitis, maculopapular rash, mucositis, hypophosphatemia, anaphylaxis, dyspnea, pleural effusion, and pain. Twenty patients were evaluable for response analysis. Two patients (2/10, 20%) achieved a confirmed partial response (both with HCC, lasting 6.9 and 17.6 months), while 9 patients (4 [40%] with HCC and 5 [41.7%] with BTC) had stable disease, with the longest duration of 9.3 months (in an HCC patient). Disease control rate is 60% in HCC and 41.7% in BTC, respectively. In this small pilot cohort, median PFS was 3.1 months (95% CI 0.8 to 4.6 months) and median OS was 5.45 months (95% CI 4.60 to 8.3 months) among BTC patients, while HCC patients median PFS was 7.8 months (95% CI 2.6 to 10.6 months) and median OS was 15.9 (95% CI 7.1 to 16.3 months). Conclusions: Combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC. Clinical trial information: NCT02821754.
The association of novel recurrent in-frame gene fusions with prognosis of diffuse gastric cancer.
Authors: Kim Hark K.
Published: January 2019

34

Background: Among the two histologic subtype of gastric cancer (GC), diffuse gastric cancer (DGC) is increasingly being considered distinct from intestinal type gastric cancer (IGC). Despite the relative importance of DGC, few whole transcriptomic analyses have been performed for this histological subtype. We therefore conducted an RNA-sequencing study to search for novel driver fusions in DGC. Methods: We conducted a whole transcriptomic and targeted RNA sequencing study of 384 Korean DGCs to identify gene fusions that may be novel prognostic markers or therapeutic targets. Targeted DNA sequencing and SNP6.0 array analyses were conducted in parallel. Results: Whole transcriptomic analyses were conducted in 80 discovery dataset tumors collected from young patients with DGC who had not been treated with chemotherapy or radiation. Twenty-five in-frame fusions were associated with DGC, four of which were recurrent in 384 DGCs based on targeted RNA sequencing and RT-PCR sequencing analyses. Three of the four recurrent fusions contained a RhoGAP domain in their 3’ partner genes. Patients with one of these three fusions have a significantly worse prognosis than those without (HR, 2.8 [95% CI, 1.5‒5.3]). The fusion that harbored a PAP2 domain in the 3’ partner gene was also identified as recurrent and poor prognostic in-frame fusions. Overall, RhoGAP and PAP2 domain-containing fusions were present in 7.5% of DGCs, but not in adjacent normal tissue, and clearly defined the worst prognosis subgroup. Their prognostic impact (adjusted HR 4.1 [95% CI, 2.1‒7.9]) was higher than, and independent of, chromosomal instability (CIN) and CDH1 mutation, which we previously identified as the strongest adverse prognostic genomic abnormalities in DGCs (adjusted HRs, 2.5 (1.5‒4.4) and 2.4 (1.3‒4.4), respectively). Our comprehensive in-frame fusion screen also identified several clinically-actionable fusions amenable to ALK or FGFR inhibition, which had not been previously associated with gastric cancer. Conclusions: Our findings may provide novel genomic insights guiding future personalized strategies for managing DGCs, given the strong prognostic impact of RhoGAP and PAP2 domain-containing gene fusions.
Hepatocellular carcinoma and liver metastasis treated by hafnium oxide nanoparticles activated by SBRT: A phase I/II trial.
Authors: Chajon Enrique , Pracht Marc , De Baere Thierry , Nguyen France , Bronowicki Jean-Pierre , Vendrely Veronique , Baumann Anne-Sophie , Valérie Laurent , Rio Emmanuel , Rolland Yan , Le Sourd Samuel , Gustin Pierre , Perret Christophe , Mornex Francoise , Peiffert Didier , Merle Philippe , Deutsch Eric
Published: January 2019

340

Background: Hafnium oxide nanoparticles, NBXTR3, were developed to increase the tumor-localized high energy deposit once activated by ionizing radiation such as stereotactic body radiotherapy (SBRT) and thus to increase tumor cell death compared to the same dose of radiation. NBTXR3 is characterized by a single intratumor/intralesional (IL) administration and fits into standard RT schedule with no change in patient’s flow, treatment protocol or equipment. Herein the preliminary results of a phase I/II clinical trial evaluating this combination in patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets). Methods: HCC and liver mets patients were treated with an IL injection of NBTXR3 followed by SBRT (15 Gy∗3 fractions). The phase I part of the trial follows a 3+3 dose escalation design at dose levels of NBTXR3 corresponding to 10%, 15%, 22%, 33% of the baseline tumor volume. This study aims primarily to identify the Recommended Dose and the incidence of early Dose Limiting Toxicities (DLTs) of NBTXR3 activated by SBRT. Secondary endpoints include assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1). Results: Enrollment is at the last dose level, 33%, and completed at 10% (6 pts), 15% (4 pts) and 22% (4 pts). So far, no early DLTs nor severe adverse events related to NBTXR3 were observed. Both CPS and APRI did not reveal important variations in accordance to NBTXR3 low toxicity. The best observed target lesions responses, among 7 evaluable HCC pts for response (mRECIST), were: 3 complete responses, 3 partial responses (PR) and 1 stable disease (SD) and among 5 evaluable liver mets pts: 1 PR, 3 SD and 1 progressive disease (RECIST 1.1). Conclusions: NBTXR3 is well tolerated at the 22% dose level with an overall positive safety profile. This innovative approach might constitute a valuable solution for pts with liver tumors beyond standard treatment lines. NBTXR3 was successful in a phase II/III in soft tissue sarcoma [NCT02379845] and is currently evaluated in head and neck [NCT01946867; NCT02901483], prostate [NCT02805894] and rectum cancers. Clinical trial information: NCT02721056.
Risk factors of hepatic failure after liver resection for perihilar cholangiocarcinoma: Importance of future liver remnant volume, body weight ratio, and impact on long-term survival.
Authors: Lee Jong Woo , Lee Jae Hoon
Published: January 2019

348

Background: Hepatic resection for perihilar cholangiocarcinoma (PHCC) is associated with high postoperative mortality. Future liver remnant volume to total liver volume ratio has been used to anticipate the risks associated with liver resection for PHCC. We sought to investigate the independent factors associated with postoperative hepatic failure (PHLF) and assess predictive value of future liver remnant volume – body weight (FLRV/Wt) ratio after resection for PHCC. Methods: This study included 287 patients who underwent major hepatectomy including caudate lobectomy with bile duct resection for PHCC between 2008 and 2015 in single center. FLRV were calculated with CT volumetry and perioperative clinical and operative data were analyzed to identify independent determinants of PHLF (grade B/C according to the International Study Group of Liver Surgery criteria) and major postoperative complications (Dindo III to IV). Results: Combined Portal vein resection was performed in 18.8%. PHLF incidence was 13.6% and 90-day mortality was 3.5%. On multivariate analysis, predictors of PHLF (p < 0.05) were FLRV/Wt ratio < 0.5 (odds ratio [OR] 9.45), ICG R15 > 15 (OR 3.72), BMI < 25.0 (OR 6.41) and R1 resection (OR 3.97). There was no significant difference of survival between two groups divided by FLRV/Wt ratio (0.5) in Kaplan-Meier analysis. There was significant difference of survival according to PHLF. In without PHLF group, 1yr, 3yr, 5yr survival were 83.1%, 45.2%, 28.1%. In PHLF B group, 1yr, 3yr, 5yr survival were 66.7%, 40.7%, 20.7% respectively. Conclusions: Insufficient FLR volume (FLRV/Wt < 0.5), ICG R15 (< 15), BMI (< 25) and R1 resection is associated with PHLF for patients with PHCC. We confirmed that PHLF is also associated with long term outcome. Preoperative assessment to patients with PHCC should be optimized to minimize the risk of PHLF. [Table: see text]
Early stage hepatocellular carcinoma treated with stereotactic body radiation therapy: A pooled analysis from two North American institutions.
Authors: Mathew Ashwathy Susan , Atenafu Eshetu G. , Owen Dawn , Maurino Chris , Brade Anthony M. , Brierley James D. , Dinniwell Robert Edward , Kim John , Cho Charles , Ringash Jolie , Wong Rebecca , Cuneo Kyle Clifford , Feng Mary Uan-Sian , Lawrence Theodore Steven , Dawson Laura A.
Published: January 2019

350

Background: To report outcomes of pooled data from patients with early stage hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) at two North American Institutions. Methods: An IRB approved collaborative review of patients with HCC treated with radical intent SBRT was conducted. Inclusion criteria included patients with Stage I-IIIA HCC (UICC/AJCC 7th Ed.) treated with SBRT (≥ 4.5 Gy/ fraction) from June 2003 until Dec 2016. Patients who were treated with SBRT were ineligible for resection, percutaneous ablative or hepatic intravascular therapies. Patients with vascular invasion and those treated with palliative intent (e.g. HCC rupture) were excluded. Overall survival, local control and toxicity of treatment were reviewed retrospectively. Results: Of 310 eligible patients, 23% were Child-Pugh (CP) class B/C (21%/2%), and 40% had failed prior liver directed therapies. The median HCC diameter was 2.4 cm (range 0.5-18.1 cm), and the median prescribed dose was 39 Gray (Gy) in 5 fractions (range: 14 - 60 Gy in 2-6 fractions). Median BED was 78.75 Gy (Range: 23.8-180.0 Gy). 8.4% of patients underwent liver transplant after SBRT. Local control at 1, 3 and 5 years was 91.5%, 82.6% and 82.6%. On multivariable analysis (MVA), the use of breath-hold motion management, but not T stage, size or dose, was significantly associated with local control (p = 0.0098). The 1, 3, and 5 year overall survival (OS) was 77.3%, 37.9% and 23.5%. Factors associated with improved OS on MVA included baseline CP A score (HR = 0.58, p < 0.0045), AFP < 10 µg/L (HR = 0.66, p = 0.0094), and transplant post SBRT (HR = 0.05, p < 0.0001). The median survival of CP A vs. B/C patients was 30.3 and 17.6 months respectively. CTCAE (v4.0) grade 3 or higher luminal gastrointestinal organ toxicity occurred in 2.5% of patients, while a decline in CP score ≥ 2 points was seen in 16.7% of patients at 3 months post SBRT. Grade 3 and above elevated liver enzymes were seen in 12.6% and 8.1% of patients at baseline and at 3 months post SBRT. Conclusions: Similar to Asian series, this North American pooled analysis found high sustained local control and excellent survival in patients with early stage HCC treated with SBRT.
Survival and cost associated with chemotherapy and chemoradiotherapy among resected pancreas cancer patients.
Authors: Vela Nivethan , Davis Laura , Cheng Stephanie Y , Hammad Ahmed , Liu Ying , Kagedan Daniel , Bubis Lev , Earle Craig , Paszat Lawrence Frank , Myrehaug Sten , Mahar Alyson L. , Mittmann Nicole , Coburn Natalie G.
Published: January 2019

351

Background: Pancreas cancer is expensive to treat, and the effectiveness of adjuvant chemotherapy (CT) and chemoradiation (CRT) following resection is debated. We compared both survival and healthcare costs by adjuvant therapy after curative-intent pancreaticoduodenectomy (PD) for pancreas adenocarcinoma (PC). Methods: All patients with resected PC in Ontario, Canada diagnosed 2004 to 2014 were identified and linked to administrative healthcare databases. Stratified Kaplan—Meier survival curves and log-rank test compared survival across treatment groups. Costs were assessed from the perspective of Ontario’s single-payer healthcare system and compared between CT and CRT. A one-year time horizon was used from the date of surgery. Results: 677 PC patients met all inclusion/exclusion criteria and underwent curative-intent PD with 77% receiving CT and 23% CRT. Median survival after resection was 21.7 and 18.9 months for CT and CRT groups, respectively. Patients receiving CRT were less likely to have high comorbidity burden (ADG ≥ 10), but were similar across other demographics. CRT patients were more likely to have margin positive disease. In a subgroup of 489 patients with margin negative disease, median survival in the node negative patients (n = 156) was 28.0 months for CRT and 24.7 months for CT (p = 0.8297, logrank). Median survival in the node positive patients (n = 333) was 20.6 months and 21.8 months for the CRT and CT patients, respectively (p = 0.9856, logrank). The median total one-year cost for CT was $52,575 (USD); CRT was $68,216 (Table 1). Conclusions: Patients who underwent adjuvant CT and CRT after PD for PC had similar overall survival, but healthcare expenditures were significantly higher in the CRT group. [Table: see text]
A multicenter cohort study of sunitinib (SU) versus imatinib (IM) dose escalation as second-line therapy in patients with gastrointestinal stromal tumors (GISTs) after disease progression of 400 mg/d IM.
Authors: Zhang Xinhua , Liu Xing , Wu Xiao Jun , Pan Zhizhong , Lu Hui-shan , He Yulong
Published: January 2019

356

Background: Lacking of robust evidence from prospective trials, whether to choose IM dose escalation or to directly change to SU in patients failure on standardized 400mg/d dosing of IM is still controversial. Methods: The aim of this study, is to compare the efficacy of sunitinib and imatinib dose escalation as second-line therapy in patients with GIST previously treated with 400mg/d IM. Data of patients with recurrent/metastatic GISTs who was treated by SU from 2008.1 to 2016.12, in three tertiary teaching hospitals in southern China were analyzed from prospectively registered databases, respectively. Time to SU failure (TTSF) was defined as from the time of disease progression of 400mg/d IM to failure of SU treatment in both groups. Results: A total of 240 patients received SU at least 8 weeks were collected. SU was given in 37.5mg continuous daily dose or 50mg 4 weeks on/2 weeks off. Data of 203 patients (male 136, female 67) with complete follow-up were analyzed. The median age was 52.6 years, ranged 20-79 years. KIT/PDGFRA mutational analysis was performed in 151 patients. KIT exon 11 and 9 mutations were found in 79 (52.3%) and 39 (25.8%) patients, respectively. PDGFRA D842V was in five patients (3.3%), and KIT/PDGFRA WT in 26 patients (17.2%). After failure on 400mg/d IM, 100 (49.3%) patients had a dose escalation to 600mg/800mg per day (IM group), and 103 directly changed to SU(SU group). The progression-free survival (PFS) of IM group and SU group was 5.8m and 16.9m, respectively ( P<0.001). Either the TTSF or overall survival (OS) on both groups was not statistically different (18.3m VS 16.9m, P=0.219; 29.42m VS 29.45m, P=0.73). None of clinical factors that was correlated with survival using regress analysis, including primary site of lesion, metastatic sites, or mutational status, etc. Conclusions: This multi-center cohort study indicated better PFS in directly changed to SU than IM dose escalation when standardized dose IM failure. However, to those continued with SU therapy after failure of dose escalation, the outcome, both time to SU failure or OS, is similar.
Racial disparities in the receipt of adjuvant chemotherapy in patients with resected stage I-III pancreatic adenocarcinoma.
Authors: Sanford Nina Niu , Xu Xiaohan , Sher David J.
Published: January 2019

357

Background: Adjuvant chemotherapy for resected pancreatic adenocarcinoma is a category 1 NCCN recommendation, however studies have shown that many patients do not go on to receive chemotherapy after definitive surgery. Whether racial disparities exist for receipt of adjuvant chemotherapy is unknown. Methods: The National Cancer Database was used to identify 28,255 patients with non-metastatic pancreatic adenocarcinoma who underwent definitive surgery between 2005-2014. Multivariable logistic regression defined adjusted odds ratio (AOR) and 95% confidence intervals (CI) of receipt of adjuvant chemotherapy by race. Additional variables included in the model were age, sex, stage, node positivity, comorbidity index, facility type and insurance. Among those receiving chemotherapy, multivariable logistic regression assessed odds of treatment with multiagent chemotherapy and among those not receiving chemotherapy, predictors of chemotherapy refusal were assessed. Results: Compared to white patients, black patients were less likely to receive adjuvant chemotherapy (AOR 0.74, 95% CI 0.64-0.85, p < 0.001) and multiagent adjuvant chemotherapy (AOR 0.80, 95% CI 0.72-0.88, p < 0.001). The disparities were limited to patients with comorbidity score of 0 and persisted when analyses were restricted to only academic cancer centers. Among 2,405 patients not treated with chemotherapy, black patients had lower odds of refusing chemotherapy (AOR 0.72, 95% CI 0.55-0.93, p = 0.01). Conclusions: In this nationally representative study, black patients were less likely to receive NCCN-guideline concordant treatment for resected pancreatic adenocarcinoma; this disparity did not appear to be driven by increased refusal of treatment by black patients. Given that differences in quality of care may contribute to disparities in cancer survival, our findings suggest that outcomes for black patients could be improved by increasing the proportion receiving guideline-concordant adjuvant chemotherapy. Further investigation is needed to identify factors leading to the observed differences in this study, such that appropriate interventions can be undertaken to mitigate this disparity.
Is rising BMI associated with an increased rate of clinically relevant pancreatic fistula after distal pancreatectomy for pancreatic adenocarcinoma?
Authors: Glazer Evan Scott , Zhou Yixuan , Drake Justin , Deneve Jeremiah Lee , Behrman Stephen W , Dickson Paxton Vandiver , Shibata David
Published: January 2019

360

Background: Clinically relevant pancreatic fistula (CR-POPF), following distal pancreatectomy (DP) remains a clinical challenge. Prior studies investigating the relationship between body mass index (BMI) and CR-POPF have yielded conflicting results. We examined this relationship utilizing our institutional database and hypothesized that BMI is associated with CR-POPF in patients having DP for pancreatic ductal adenocarcinoma (PDAC). Methods: Patients who underwent DP for PDAC at a single institution from 2007 to 2018 were retrospectively reviewed. A CR-POPF was defined as ISGPS grade B or C fistula. Uni- and multi-variable logistic regression analysis to assess factors associated with CR-POPF following DP was performed, controlling for factors such as gland texture, operative drain placement, gender, and smoking status. Results: 78 patients met the inclusion criteria. 51% were female, 51% were Caucasian, and the average age was 59 ± 15 years. The median BMI was 26 (interquartile range 24 to 29). Overall, 19% (n = 15) of patients had a CR-POPF. With a mean follow up 2.8 ± 2.5 years, the presence of a CR-POPF was not associated with long-term survival (P = 0.17). On univariable logistic regression, older age was associated with a decreased risk of CR-POPF (OR = 0.95, P = 0.015) while increasing BMI was associated with an increased risk of CR-POPF (OR = 1.1, P = 0.044). After controlling for multiple factors on multivariable logistic regression analysis, BMI (OR = 1.12, P = 0.035) was the only factor associated with development of a CR-POPF while older age (OR = 0.94, P < 0.001) was slightly protective of CR-POPF development. Conclusions: For patients undergoing DP for PDAC, increasing BMI is associated with an increased risk of CR-POPF, independent of other factors. These findings should be considered during preoperative counseling. Although there is no specific cut-off for the association between BMI and CR-POPF, efforts to diminish the risk of CR-POPF should be focused on patients with higher BMI based on this data.
Outcomes of tyrosine kinase inhibitors (TKI) after immunotherapy in unresectable or advanced hepatocellular carcinoma (HCC) patients.
Authors: Yau Thomas Cheung , Tang Vikki , Chan Jess , Kwok Gin Wai , Chiu Joanne , Leung Roland Ching-Yu , Li Bryan , Cheung Tan To
Published: January 2019

361

Background: The outcomes of tyrosine kinase inhibitor(TKI) treatment after immune checkpoint inhibitors (PD-1i, PD-L1i, CTLA-4i) in unresectable/advanced HCC population is largely unknown. Methods: Retrospective analysis of advanced HCC patients treated with immune checkpoint inhibitors followed by TKI therapy at Queen Mary Hospital, Hong Kong were reviewed for the outcomes. Patients received locoregional therapy immediately after immunotherapy were excluded. Results: From January 2016 to July 2018, 30 HCC patients (83% of HBV, 80% of Child Pugh A, 83% of EHS/ MVI, median AFP=1,353ng/mL) who received TKI (11 lenvatinib, 10 sorafenib, 6 regorafenib, 3 axitinib) after immunotherapy were identified. TKI post-immunotherapy ("index TKI") was administered as third-line or beyond in 70% of patients. At the time of analysis (September 2018), median duration of index TKI was 72 days (IQR 36- 119∗) (∗3 patients were still receiving TKI). AFP declined in 53% of patients and the median change from baseline to nadir was -25% (IQR -65% to +6%). 40% of patients received subsequent systemic therapy. Median OS from index TKI was 602 days (95%CI 124-not reached; death event rate: 47%). 3 patients achieved partial response to TKI and they had at least stable disease with the previous immunotherapy. No unexpected safety issues of TKI and death related to adverse events were noted (table). Conclusions: TKI is active with good tolerabilty following immunotherapy in advanced HCC patients.[Table: see text]
A nationwide multicenter study in patients with unresectable hepatocellular carcinoma treated with lenvatinib in real world practice in Japan.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Kaneko Shun , Kimura Toru , Marusawa Hiroyuki , Arai Hirotaka , Abe Takehiko , Kimura Hiroyuki , Tsuji Keiji , Furuta Koichiro , Ogawa Chikara , Narita Ryoichi , Kojima Yuji , Akahane Takehiro , Uchida Yasushi , Yoshida Hideo , Kobashi Haruhiko , Kusakabe Atsunori , Joko Kouji , Izumi Namiki ,   The Japanese Red Cross Liver Study Group
Published: January 2019

364

Background: Lenvatinib(LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. A few results from a large sample size cohort of LEN therapy in real world practice has been reported. Therefore, we performed a retrospective nationwide multicenter study. Methods: A total of 116 u-HCC patients received LEN from March 2018 at 14 sites in Japan were registered. Tumour assessments in accordance with RECICT ver1.1 and modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: Median age was 72 (46-91)years, 88 (75.9%) patients were male, and median body weight was 60 (30-94) kg. The baseline liver function was Child-Pugh class A in 106 (91.4%) patients. Seventy-three (62.9%) patients were BCLC stage C. As the 2nd-line therapy (after sorafenib), 28 (24.1%) patients received LEN and 17 (14.7%) patients did as the 3rd-line (after regorafenib). Median observation time was 2.5 months and one patient died from HCC progression. The imaging findings of 49 (42.2%) patients were evaluated at 4-8weeks. Based on mRECIST, CR was shown in 3 (6.1%), PR in 14 (28.6%), SD in 23 (46.9%), and PD in 6 (12.2%). In the 3 patients, target lesions of liver showed PR, however bone metastases had progressed. [overall response rate (ORR) 34.7%, disease control rate (DCR) 81.6%]. ORR and DCR of tyrosine kinase inhibitor (TKI) naïve patients (n = 26) were 34.6% and 80.8%, while those of TKI experienced (n = 23) were 34.8% and 82.6%. The most common any-grade AEs were hypertension (52.0%), diarrhoea (32.1%), decreased appetite (63.5%) and fatigue (49.4%). Hand-food skin reaction (HFSR) was observed in 28% of patients. Conclusions: The efficacy of LEN therapy in real world practice in Japan was similar to the phase 3 clinical trial, even though elderly patients with lower body weight were included in this study. The incidence of HFSR during LEN in real world practice was lower than that of the sorafenib group in the phase 3 trial of LEN. Decrease appetite and fatigue must be carefully monitored and managed during LEN therapy.