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Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

International audience; Simple Summary Radioembolization is a kind of internal radiation therapy which is currently used in non-operable HCC. Several radiolabeled product can be used as Y-90-loaded microspheres or less frequently radiolabeled lipiodol either with iodine 131 (in the past) or currently with rhenium 188 (Re-188). Currently used Re-188-labeled compounds are limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to Re-188-SSS lipiodol, a new and more stable compound. Method: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety. Secondary endpoints included bio-distribution and response evaluation. Results: Fourteen heavily pre-treated HCC patients were treated in Level 1 (n = 6), Level 2 (n = 6), and Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity. The study was prematurely discontinued unrelated to clinical outcomes. Cumulative urinary elimination and fecal eliminations at 72 h were very low, confirming high in vivo stability. Partial response occurred in 37.5% of the patients receiving 3.6 GBq of Re-188-SSS lipiodol or more. Conclusion: As the 3.6 GBq activity proved to be safe, it will be used in an ongoing Phase 2 study. Background: Despite the wide development of Y-90-loaded microspheres, Re-188-labeled lipiodol is still being used for radioembolization of hepatocellular carcinoma (HCC). However, the use of this latter compound is limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to Re-188-SSS lipiodol, a new and more stable compound. Method: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety based on Common Terminology Criteria for Adverse Events (AEs) of Grade >= 3 within 2 months. Secondary endpoints included bio-distribution assessed by scintigraphy quantification from 1 to 72 h, tumor to non-tumor uptake ratio (T/NT), as well as blood, urine and feces collection over 72 h, dosimetry, and response evaluation (mRECIST). Results: Overall, 14 heavily pre-treated HCC patients were treated using a whole liver approach. The mean injected activity was 1.5 +/- 0.4 GBq for activity Level 1 (n = 6), 3.6 +/- 0.3 GBq for Level 2 (n = 6), and 5.0 +/- 0.4 GBq for Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity (one liver failure; one lung disease). The study was prematurely discontinued unrelated to clinical outcomes. Uptake occurred in the tumor, liver, and lungs, and only sometimes in the bladder. The T/NT ratio was high with a mean of 24.9 +/- 23.4. Cumulative urinary elimination and fecal eliminations at 72 h were very low, 4.8 +/- 3.2% and 0.7 +/- 0.8%, respectively. Partial response occurred in 21% of patients (0% in the first activity level; 37.5% in the others). Conclusion: The high in vivo stability of Re-188-SSS lipiodol was confirmed, resulting in encouraging responses for a Phase 1 study. As the 3.6 GBq activity proved to be safe, it will be used in a future Phase 2 study.

Background: In the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) single-arm phase 2 trial, concomitant chemotherapy and selective internal radiotherapy (SIRT) showed antitumor activity as a first-line treatment of unresectable intrahepatic cholangiocarcinomas (ICCs). In this sub-analysis, we aimed to evaluate one of the secondary endpoints, the health-related quality of life (QoL), evaluated with an EORTC QLQ-C30 instrument at the baseline and during treatment. Methods: The MISPHEC trial included treatment-naïve patients with an unresectable ICC between November 2013 and June 2016. Patients received concomitant first-line chemotherapy with cisplatin and gemcitabine for 8 cycles, SIRT was administered during cycle 1 (for patients with unilobar disease) or cycles 1 and 3 (for patients with bilobar disease) using glass Yttrium-90 microspheres. We evaluated the QoL—measured by the QLQ-C30 questionnaire—at the baseline, every 8 weeks during chemotherapy and follow-up, between 12 and 15 weeks after embolization and every 12 weeks after a liver resection if applicable. Results: A total of 41 patients were included, of which 34 completed questionnaires at the baseline. No clinically significant changes in the global health score or the sub-scales of the QLQ-C30 were observed during follow-up. The physical, social and role function mean score worsened during treatment and fatigue, nausea and pain scores increased although the differences were not clinically significant. In patients undergoing subsequent surgery, the QoL was not impaired. Conclusions: A combination of SIRT and chemotherapy with gemcitabine and cisplatin as the first-line treatment of unresectable ICCs was found to maintain the QoL.

Background Selective internal radiation therapy (SIRT) is applied to hepatocellular carcinoma (HCC), a disease with increased incidence in the elderly. However, SIRT has rarely been specifically studied in elderly population. The aim of this study was to investigate efficacy and safety of SIRT in elderly HCC patients. Methods We studied retrospectively data from patients treated with SIRT for HCC. Clinical and laboratory data were retrieved. We used 70-years old as threshold between younger and elderly populations, to compare outcomes. Results A total of 222 patients treated with SIRT for HCC were studied, of which 134 patients were younger and 88 older. Median overall survival (OS) was not significantly different between younger and elderly group: 15.6 months (95% CI, 11.7-19.5) and 14.8 months (95% CI, 9.4-20.3) (P = 0.86). Age was not associated with OS in multivariable analysis, with a Hazard ratio of 1.09 (95% CI, 0.82-1.45, P = 0.55). Results of progression-free survival and responses were also similar in both groups. Toxicities were similar between the two groups, including the occurrence of radioembolization-induced liver disease (11.5 vs. 11.4%, P = 0.97). Conclusion SIRT appears to be a well-tolerated treatment with the same efficacy in elderly compared to younger patients in HCC. Our study is the first to study its impact with glass microspheres. This warrants confirmation in large prospective studies.

International audience; BACKGROUND: All randomised phase 3 studies of selective internal radiation therapy for advanced hepatocellular carcinoma published to date have reported negative results. However, these studies did not use personalised dosimetry. We aimed to compare the efficacy of a personalised versus standard dosimetry approach of selective internal radiation therapy with yttrium-90-loaded glass microspheres in patients with hepatocellular carcinoma.METHODS: DOSISPHERE-01 was a randomised, multicentre, open-label phase 2 trial done at four health-care centres in France. Patients were eligible if they were aged 18 years or older and had unresectable locally advanced hepatocellular carcinoma, at least one measurable lesion 7 cm or more in size, a hepatic reserve of at least 30% after selective internal radiation therapy, no extrahepatic spread (other than to the lymph nodes of the hilum, with a lesion 5% of patients) grade 3 or higher adverse events were ascites (one [3%] patient who received personalised dosimetry vs two [10%] patients who received standard dosimetry), hepatic failure (two [6%] vs none), lymphopenia (12 [34%] vs nine [43%]), increased aspartate aminotransferase concentrations (three [9%] vs two [10%]), increased alanine aminotransferase concentrations (three [9%] vs none), anaemia (two [6%] vs one [5%]), gastrointestinal haemorrhage (none vs two [10%]), and icterus (none vs two [10%]). One treatment-related death occurred in each group.INTERPRETATION: Compared with standard dosimetry, personalised dosimetry significantly improved the objective response rate in patients with locally advanced hepatocellular carcinoma. The results of this study suggest that personalised dosimetry is likely to improve outcomes in clinical practice and should be used in future trials of selective internal radiation therapy. FUNDING: Biocompatibles UK, a Boston Scientific Group company.

370 Background: When combined to preoperative radiation therapy (RT), CP and FFX regimen provide both high complete resection (R0) rate for EC/EGJ cancer (Adenis, ASCO 2022). However, it appeared that neoadjuvant chemoradiation (nCRT) with CP is associated with a severe postoperative morbidity rate higher than expected. We present here the expanded safety and efficacy analyses from the PROTECT trial. Methods: PROTECT is a randomized, phase 2 trial which included stage II/III and ECOG PS ≤2 EC or Siewert I-II EGJ cancers. Patients (pts) received FFX or CP with concurrent RT (41.4Gy, 1.8Gy, 23 fractions), followed by surgery 4-8 weeks after completion of nCRT (Messager, BMC Cancer 2016). Co-primary endpoints were proportion of R0 rate and proportion of Clavien-Dindo severe postoperative morbidity. Main secondary endpoints were nCRT and postoperative safety (NCI CTCAE v.4), DFS and OS. Results: 41/50 (82%) and 39/50 (78 %) pts received the planned chemo cycles and concurrent RT in FFX and CP arms, respectively. Grade (gr.) 3–4 AEs related to nCRT (FFX 14/50, 28%; CP 14/50, 28%) occurring in ≥5% of pts included lymphopenia (n=3, 6%; n=4, 8%), neutropenia (n=1, 2%; n=3, 6%), fatigue (n=2, 4%; n=0) and esophagitis-related to RT (n=1, 2%; n=1, 2%). No death was reported during nCRT. Surgery (FFX and CP; mini invasive: 15 and 15, hybrid: 22 and 21, open: 7 and 12) was performed in 44 and 48 pts, in FFX and CP groups, respectively. The main gr. III-V surgical complications (Clavien-Dindo scale) occurring in ≥5% of pts included esophageal fistula (n=2/43 evaluable pts, 6%; 8/48, 17%), conduit necrosis (n=2, 5%; n=1, 2%), ARDS (n=3, 7%; n=3, 6%), pleural effusion (n=3, 7%; n=4, 8%), and haemorrhage (n=0; n=3, 6%). There were no postoperative deaths. With a median follow-up of 54m, median DFS were 12.3m and 20m (HR=0.84; 95%CI: 0.52-1.35; p=0.48) and median OS were 31.7m and 45.8m (HR=0.79; 95%CI: 0.47-1.32; p=0.36) in FFX and CP arms, respectively. Prognostic factors significantly associated to DFS in univariate analysis were: R0 resection, TRG1-2 and ypT0N0 status. Conclusions: A higher than expected number of severe esophageal fistula was observed in the CP arm. We could not demonstrate a significant benefit of CP compared to FFX in terms of survival outcomes, but the study was not primarily designed to specifically address this issue. Clinical trial information: NCT02359968 .

Simple Summary SIRT, also known as radioembolization, is a new treatment for hepatocellular carcinoma. However, the precise role is still not clearly determined. Here, we describe how a new score, ALBI, used to better assess liver functions, can help to select patients for this treatment. We clearly showed that the ALBI grade was associated with toxicity and survival after this treatment. Abstract Background: Selective internal radiation therapy (SIRT) is an innovative treatment of hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score was designed to better evaluate liver functions in HCC. Methods: We studied, retrospectively, data from patients treated with SIRT for HCC. The primary endpoint was the occurrence of radioembolization-induced liver disease (REILD). The secondary endpoint was overall survival (OS). Results: 222 patients were studied. The ALBI grade 1 patients had significantly less REILD (3.4%) after the first SIRT than ALBI grade 2 or 3 patients (16.8%, p = 0.002). Of the 207 patients with data, 77 (37.2%) had a worsening of ALBI grade after one SIRT. The baseline ALBI grade was significantly associated with OS (p = 0.001), also in the multivariable analysis. The ALBI grade after the first SIRT was significantly associated with OS (p ≤ 0.001), with median OS of 26.4 months (CI 95% 18.2–34.7) for ALBI grade 1 patients (n = 48) versus 17.3 months (CI 95% 12.9–21.8) for ALBI grade 2 patients (n = 123) and 8.1 months (CI 95% 4.1–12.1) for ALBI grade 3 patients (n = 36). Conclusions: The baseline ALBI grade is a strong predictor of REILD. The baseline ALBI score and variations of ALBI are prognostic after SIRT.

4015 Background: Preoperative CRT with a FU/platinum regimen has been used for years for esophageal or junctional cancer before the CP regimen became a standard of care following the results of the CROSS study (van Hagen 2012). We aimed at evaluating the complete resection (R0) rate and severe postoperative morbidity rate associated with these 2 neoadjuvant regimens, each being combined with the radiation (RT) regime used in the CROSS trial. Methods: PROTECT is a multicenter, randomized, non-comparative, phase 2 trial (NCT02359968) in patients (pts) with resectable esophageal or Siewert type I-II junctional cancer, stage II (T1-2N1 or T3N0) or stage III (T3N1 or T4anyN) tumors (UICC-7 classification), and ECOG PS ≤2. Following randomization (balanced by ECOG PS 0 vs 1-2, stage II vs III, squamous-cell (SCC) vs adenocarcinoma (ADK), center), pts received CP (AUC2 CBP plus PCL 50mg/m² / week x 5 weeks), or Fx (FU 400 mg/m² bolus Day 1, then FU 1600 mg/m² continuous infusion over 2 days, plus OX 85 mg/m², and Folinic acid 200 mg/m², 2-h infusion, Day 1; 3 cycles every 2 weeks). RT technique was similar in both arms: 3D-conformal as published in the CROSS trial or IMRT (n = 35); total dose of 41.4Gy, 5 fractions of 1.8Gy / week, starting at Day 1 of chemotherapy. Surgery was performed 4 to 8 weeks after completion of CRT through a transthoracic or mini-invasive approach with a two field extended lymphadenectomy. Co-primary endpoints were R0 (failure: R1 or disease progression under CRT), and severe postoperative morbidity rate ≤30 days after surgery (Clavien-Dindo grade ≥ III). Based on a Bryant and Day 2-stage design (p0 = 75% and p1 = 90% for resection; p0 = 45% and p1 = 25% for morbidity; α = 10% and β = 15%), 48 evaluable pts were required by arm. Results: 100/104 pts recruited from 02/2015 to 08/2020, started the study treatment: 50 CP & 50 Fx. Overall, median age = 64 (range, 33-79); 82/100 males; 62 ADK and 38 SCC; 66 esophageal and 34 junctional site; 31 stage II; 68 stage III, 1 Nx. R0 resection was obtained in 46/50 CP pts (92.0%, 95% CI: 80.8-97.8%), and in 42/48 Fx pts (87.5%, 74.8-95.3%); 2 non evaluable pts because of event unrelated to disease progression. Severe postoperative adverse events (AEs) occurred in 34/91 pts who underwent surgery: 21/48 CP (43.8%, 29.5-58.8%) and 13/43 Fx (30.2%, 17.2-46.1%). Severe AEs were respiratory disorders (CP 26%; Fx 26%), esophageal fistula (CP 18%; Fx 6%), infection (CP 5%; Fx 3%), haemorrhage (CP 5%; Fx 0%) and gastric tube necrosis (CP 6%; Fx 3%). 5 pts died from AEs (3 CP, 2 Fx). A TRG1-2 was observed in 29/48 (60.4%, 95% CI: 44.3-74.2%) CP pts, and in 19/43 (44.2%, 29.1-60.1%) Fx pts. Conclusions: When combined to preoperative radiation therapy at 41.4Gy, both regimens (CP and Fx) provided short-term benefit on R0 resection; however, CP is associated with a severe postoperative morbidity rate higher than expected. Clinical trial information: NCT02359968.

International audience; Fluoropyrimidine (FP) plus platinum chemotherapy has been recently established as a second-line (L2) preferred option in advanced biliary tract cancer (aBTC) (ABC-06 phase III trial). However, the overall survival (OS) benefit was limited and comparison with FP monotherapy was not available. Our aim was to assess the OS of patients treated with a FP monotherapy compared to a doublet with irinotecan or platinum in L2. We performed a retrospective analysis of two large multicenter prospective cohorts: a French cohort (28 centers) and an Italian cohort (9 centers). All consecutive patients with aBTC receiving FP-based L2 after gemcitabine plus cisplatin/gemcitabine plus oxaliplatin L1 between 2003 and 2016 were included. A subgroup analysis according to performance status (PS) and an exploratory analysis according to platinum sensitivity in L1 were planned. In the French cohort (n = 351), no significant OS difference was observed between the FP monotherapy and doublet groups (median OS: 5.6 vs 6.8 months, P = .65). Stratification on Eastern Cooperative Oncology Group (ECOG) PS showed similar results in PS 0-1 and 2. Median OS was not different between FP monotherapy, platinum- and irinotecan-based doublets (5.6 vs 7.1 vs 6.7 months, P = .68). Similar findings were observed in the Italian cohort (n = 174) and in the sensitivity analysis in pooled cohorts (n = 525). No L2 regimen seemed superior over others in the platinum resistant/refractory or sensitive subgroups. Our results suggest that FP monotherapy is as active as FP doublets in aBTC in L2, regardless of the patient PS and country, and could be a therapeutic option in this setting.

Background Approximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10–15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low ( Objectives and endpoints of the phase II study Our main objective is to investigate the efficacy, in term of CRR (R0-R1), of treatment intensification in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after at least 2 months of induction sys-CT. Patients will receive either HAI oxaliplatin plus systemic FOLFIRI plus targeted therapy (i.e. anti-EGFR antibody or bevacizumab) or conventional sys-CT plus targeted therapy (i.e. anti-EGFR or antiangiogenic antibody). Secondary objectives are to compare: progression-free survival, overall survival, objective response rate, depth of response, feasibility of delivering HAI oxaliplatin including HAI catheter-related complications, and toxicity (NCI-CTCAE v4.0). Methods This study is a multicenter, randomized, comparative phase II trial (power, 80%; two-sided alpha-risk, 5%). Patients will be randomly assigned in a 1:1 ratio to receive HAI oxaliplatin combined with systemic FOLFIRI plus targeted therapy (experimental arm) or the best sys-CT plus targeted therapy on the basis of their first-line prior sys-CT history and current guidelines (control arm). One hundred forty patients are required to account for non-evaluable patients. Trial registration ClinicalTrials.gov, (NCT03164655). Trial registration date: 11th May 2017.

International audience; Importance - Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge. Objective - To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC. Design, setting, and participants - This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019. Interventions - Concomitant first-line chemotherapy with cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2 (gemcitabine reduced to 300 mg/m2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y90 microspheres. Main outcomes and measures - Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria. Results - Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection. Conclusions and relevance - Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.

International audience; Purpose Selective internal radiation therapy (SIRT) has been proposed for combination with immunotherapy to treat hepatocellular carcinoma (HCC). However, the toxicity of radiation toward lymphocytes is understudied after SIRT. The aim of this study was to describe variations of lymphocytes following SIRT and their potential prognostic impact.Materials and Methods This is a retrospective cohort study of 164 patients treated with SIRT for HCC. Lymphocyte count and neutrophil-to-lymphocyte (NLR) ratio were evaluated at baseline and at 3 months. Primary endpoint was overall survival (OS).Results Median baseline lymphocyte count was 1.32 Giga/Liter (G/L) (standard deviation (SD) 0.64) at baseline versus 0.68 G/L (SD 0.41) at 3 months. The mean decrease of lymphocyte count was - 44% (standard deviation 0.24). At 3 months, only 21% of patients had normal (1 G/L or more) lymphocyte count, and 23% had lymphocyte count < 0.5 G/L. NLR at 3 months was significantly and independently associated with OS in multivariate Cox model. Median OS was 9.9 months (95% confidence interval (CI) 6.2-13.5) for patients with NLR at 3 months higher than 7.2 compared to 19.9 months in patients with an NLR lower that the 7.2 threshold (95% CI 16.3-23.3) (p = 0.003).Conclusions The decrease in lymphocytes was frequent and deep after SIRT for HCC. NLR increase at 3 months was associated with poor survival.

International audience; Purpose - Radioembolization (RE) is a promising treatment option for biliary tract cancers (BTC). We report here the largest series to date using this treatment modality. Methods - We retrospectively studied data from 64 patients treated outside prospective clinical trial at our institution. We studied baseline characteristics as potential prognostic factors. We studied dose delivered to the tumor as predictive factors of outcomes in patients not receiving concomitant chemotherapy. Results - The Progression-Free Survival and Overall Survival (OS) were 7.6 months [95% Confidence Interval (CI): 4.6-10.6] and 16.4 months [95% CI: 7.8-25.0] in the whole cohort. The factors independently associated with OS in multivariable analysis were the primary localization of ICC (HR = 0.27, 95% CI: 0.11-0.68, p = 0.005) and a PS > 0 (HR = 2.21, 95% CI: 1.11-4.38, p = 0.024). During follow-up, 12 patients (19%) underwent surgery following downstaging, with a median OS of 51.9 months. In patients not treated with concomitant chemotherapy (n = 31), OS was significantly higher in patients with a dose delivered to the tumor 260Gy or higher than in patients with a dose delivered to the tumor lower than 260Gy (median 28.2 vs 11.4 months, log-rank p = 0.019). Conclusion - Our results confirm that RE is a promising treatment modality in BTC. A high proportion of patients could be downstaged to surgery, with promising long-term survival. Dose delivered to the tumor correlated with clinical outcomes when chemotherapy was not used concomitantly.

Background Sorafenib is the standard treatment of advanced hepatocellular carcinoma. Because of its unique toxicities, improving patients' tolerance merits close follow-up. Nurses can play a crucial role by leading a patient educational program (EP). Objectives The aim of this study was to assess whether adding EP to usual care (UC) improves patient's care. Methods Since 2011, oncologists referred patients treated by sorafenib to the EP led by clinical nurses. The EP included a visit before the first administration, weekly telephone calls, and a visit with the nurse before each oncologist consultation. We retrospectively compared patients in the EP with those in UC followed by an oncologist and patients included in a clinical trial. Results Since 2005, 129 patients were treated with sorafenib for hepatocellular carcinoma: 31 in the EP (24%), 22 in a clinical trial (17%), and 76 with UC (59%). Seventy-one percent of the patients in the EP had toxicities identified during a telephone call, which prompted symptomatic measures in 65% of the patients, leading to treatment modification before the planned on-site visit in 29% of the patients. Educational program patients required fewer dose reductions (39% vs 61% for UC, P = .04), and median time to first dose reduction was shorter with EP than with UC (25 vs 45 days, P = .036). Conclusions This study suggests a clinical benefit of EP related to improved toxicity management of sorafenib that resulted in fewer dose reductions. Implications for practice Patients treated with sorafenib may benefit from an EP. Different types of EP should be compared prospectively, focusing on patients' quality of life.

Introduction Hepatic arterial infusion chemotherapy (HAIC) is a treatment used for liver metastases (LM) of colorectal cancer (CRC). Because of its technical conditions, it has been used in only a few experienced centers in France. Our aim was to evaluate its feasibility, efficacy and tolerance in 4 centers. Methods Clinical, biological, and radiological data of patients treated with HAIC for unresectable LM from CRC in 4 institutions from October 2011 to January 2016 were retrospectively analyzed. Results Sixty-one patients with unresectable LM from CRC were included. Patients had previously received systemic chemotherapy in 95% of patients and 82.8% had previous oxaliplatin treatment. Oxaliplatin was administered using an intra-arterial route combined with intravenous (I.V.) Five-fluorouracil (5-FU) with leucovorin alone in 43.3% of patients, or combined with other I.V. chemotherapies or monoclonal antibodies in 56.7% of patients. Grade 3 to 4 clinical toxicities were reported in 16% of patients, including 9.8% of neurotoxicity, and Grade 3 to 4 biological toxicities were reported in 24.6% of patients including 22.2% with neutropenia. Catheter-related complications were observed in 31.1%. Tumor response rate in first- and second-line was 26.5% and third- and fourth-line was 11%. Median overall survival (OS) in first- and second-line was 13.5 months and third- and fourth-line was 8.3 months (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.39-1.12; P = .1729). Median progression-free survival (PFS) in first- and second-line was 9 months and third- and fourth-line were 6 months (HR, 0.53; 95% CI, 0.18-0.659; P = .0037). A secondary R0 resection was possible in 10 cases (16.4%) allowing a 2-year survival of 80%. Conclusion These data confirm that in centers that recently developed HAIC using oxaliplatin, this treatment is feasible and has acceptable tolerance. The results, in terms of hepatic PFS, PFS, OS, and the rate of secondary resections of LM, are in the range of published data, and they confirm the interest of HAIC in patients in progression after multiple I.V. treatments.

International audience; Purpose: This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study.Methods: Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism.Results: The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity.Conclusion: 188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.

International audience; Les anti-PD-1 s’imposent dernièrement comme un traitement de référence dans de nombreux cancers métastatiques. Ils présentent l’avantage d’une efficacité significative doublée d’un profil de toxicité favorable en monothérapie. Les taux et durées de réponse sont toutefois très variables, ce qui implique, vu leur coût, d’identifier des biomarqueurs prédictifs de réponse. Dans cette revue de la littérature, nous nous intéressons aux biomarqueurs de réponse des immunothérapies anti-PD1 et anti-CTLA-4. L’expression de PD-L1 par les cellules tumorales et du micro-environnement évaluée par immunohistochimie est prédictive de réponse pour certains cancers mais reste une approche mal standardisée avec différents anticorps, différents seuils de positivité et différentes cibles (tumeur ou micro-environnement). Il s’agit aussi d’une expression dynamique au cours du temps et hétérogène donc souvent discordante entre biopsies et pièces opératoires. Les lymphocytes circulants pourraient représenter un biomarqueur prédictif notamment via la mesure du ratio polynucléaires neutrophiles sur lymphocytes (NLR), ratio simple à réaliser en pratique courante. Un taux de néoantigènes élevé serait également associé à une réponse plus importante ce qui expliquerait les taux de réponses particulièrement élevés des tumeurs avec instabilité micro-satellitaire. Des signatures génomiques pourraient également prédire la sensibilité aux anti-PD1. Par ailleurs, la présence de certaines bactéries de la flore intestinale favoriserait la réponse immunitaire antitumorale même si le mécanisme demeure mal compris. Enfin, des signatures d’expression de cytokines, médiatrices de la réponse immune, pourraient constituer des biomarqueurs pertinents. Plusieurs biomarqueurs de réponse potentiels semblent donc intéressants mais aucun n’est encore prospectivement validé à ce jour.

4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after > one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with >2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease >17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.

319 Background: NBTXR3, a first-in-class radioenhancer composed of functionalized hafnium oxide nanoparticles, is administered by one time intratumoral injection (ITI) and activated by radiotherapy (RT), such as stereotactic body RT (SBRT). NBTXR3 increases RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. SBRT is well-tolerated in hepatocellular carcinoma (HCC) or liver metastases (mets) and a valuable alternative for patients not eligible for surgery or radiofrequency ablation. However, energy dose deposit to tumor cells is limited due to potential toxicity to surrounding healthy tissues. Patients with unresectable liver cancers including patients with liver or renal dysfunction might benefit from NBTXR3. A Phase 1 clinical trial was conducted to evaluate the safety and Recommended Phase 2 Dose (RP2D) of NBTXR3 activated by SBRT [NCT02721056] in these patients, here we report the results. Methods: A 3+3 dose escalation scheme tested 5 NBTXR3 levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 ITI was followed by SBRT (45 Gy / 3 fractions / 5-7 days or 50 Gy / 5 fractions / up to 15 days) in patients with HCC or liver mets. Primary endpoints included RP2D determination and early DLT incidence. Secondary endpoints include safety profile, liver disease scores evolution, and early efficacy by response rate (mRECIST for HCC/RECIST 1.1 for liver mets). Results: 23 patients were treated: 6 patients at 10% (2 SBRT doses tested due to organ constraints), 4 patients each at 15% and 22% (due to fiducial displacement and ITI shift), 3 patients at 33% and 6 patients at 42%. No early DLT was observed at any dose level. 1 SAE (grade 3 late onset bile duct stenosis) related to NBTXR3 and RT occurred at 22%. There were 11 AEs related to NBTXR3 and/or ITI, of which grade 3 AEs were: 2 abdominal pain (ITI related; 15%) and 1 late onset bile duct stenosis (22%), lesion close to the bile duct. No NBTXR3 or ITI related grade 4-5 AEs were observed. RT related AEs were as expected with SBRT. No clinically meaningful changes in Child-Pugh score or APRI were observed post-treatment. CT-scan showed NBTXR3 present within the tumor without leakage to surrounding healthy tissues. Best observed responses (MRI) in injected target lesions from HCC patients (n = 15) were 5 CRs (33.3%), 5 PRs(33.3%), 1 SD (6.7%), 2 NE (13.3%), 2 patients did not have post baseline MRI and for liver mets (n = 8) were 5 PRs (62.5%), 2 SD (25.0%) and 1 NE (12.5%). Conclusions: No early DLTs were observed and NBTXR3 demonstrated a good safety and tolerability profile. The RP2D was determined to be 42% of tumor volume. Initial efficacy is promising and highlights the potential for NBTXR3 to address an unmet medical need in patients with unresectable primary or metastatic liver cancers. Clinical trial information: NCT02721056.

Resume Introduction Le sorafenib est le standard de traitement du carcinome hepatocellulaire (CHC) avance. Ce medicament est administre par voie orale et associee a une toxicite significative. Nous avons cherche a ameliorer le suivi par l’oncologue medical (OM) en impliquant des infirmieres cliniciennes dediees (ID). Patients et methodes Depuis janvier 2011, les patients sont vus par les ID pendant une heure avant le debut du traitement, puis suivis toutes les semaines par des appels telephoniques. Dans cette etude, nous avons compare de maniere retrospective les patients suivis par les ID avec ceux suivis en OM ou en essai therapeutique. Resultats Depuis 2008, 129 patients ont ete traites dans notre institution par sorafenib pour CHC, 31 (24 %) avec suivi par ID, 22 (17 %) dans un essai et 76 (59 %) en OM. Les patients suivis par les ID ont necessite moins de reduction de dose (39 % vs 61 % en OM, p = 0,04). Le temps median jusqu’a la premiere diminution de dose etait plus court (25 jours vs 45 jours, p = 0,04). Il y avait une tendance a moins de pause de traitement (19 % vs 34 %, p = 0,13) et vers moins d’arret du traitement pour toxicite (26 % vs 36 %, p = 0,33). Cependant, il n’y avait pas de difference dans la survenue de toxicite severe (48 % pour ID vs 42 % pour OM, p = 0,73). Conclusion Bien que retrospective, cette analyse suggere un interet du suivi par ID, avec une meilleure gestion des effets indesirables qui conduit a une reaction plus rapide et moins de reductions posologiques.

International audience; BACKGROUND & AIMS: Efficacy of radioembolization is derived from radioinduced damage, whereas tumour dosimetry is not considered as yet in prospective clinical trials. OBJECTIVES: This study evaluates the impact of tumour dose (TD), based on (99m) Tc macroaggregated albumin (MAA) quantification, on response and overall survival (OS). MATERIALS AND METHODS: We consecutively included 85 patients with hepatocellular carcinoma treated with (90) Y-loaded glass microspheres. TD was calculated using a quantitative analysis of the MAA SPECT/CT. Responses were assessed after 3 months using the European Association for the Study of the Liver criteria. OS was assessed using Kaplan-Meier tests. RESULTS: Response rate was 80.3% on lesion-based analysis (n=132), and 77.5% on patient-based analysis. The response rate was only 9.1% for patients with TD

537 Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056]. Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1). Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD. Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.

Avelumab is a human anti-PD-L1 IgG1 monoclonal antibody that has shown antitumor activity in early phase studies in advanced/metastatic gastric/gastroesophageal junction cancer, including as first-line maintenance therapy. Here, we describe the design of JAVELIN Gastric 100 (NCT02625610), an open-label, Phase III trial. A total of 499 patients with locally advanced/metastatic HER2- gastric/gastroesophageal junction cancer adenocarcinoma, who had achieved at least stable disease following 12 weeks of first-line oxaliplatin/fluoropyrimidine chemotherapy, have been randomized 1:1 to receive avelumab maintenance therapy or continue chemotherapy. The primary objective is to demonstrate superior overall survival in all randomized patients or in the PD-L1+ population. Secondary objectives are to demonstrate superiority for progression-free survival and objective response rate, compare quality of life measures, and determine safety.

This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection ofResults of the first six patients included are reported. Analysis of theThe mean injected activity of

International audience; Purpose: Selective internal radiation therapy (SIRT) appears to be an interesting treatment possibility for locally-advanced intrahepatic cholangiocarcinoma (ICC), yet the appropriate dosimetry has never been evaluated in this context.Methods: We retrospectively studied data from 40 patients treated at our institution with 90Y-loaded glass microsphere SIRT combined with chemotherapy for inoperable ICC as first-line treatment. Macroaggregated albumin (MAA)-based single-photon emission computed tomography (SPECT)/computed tomography (CT) quantitative analysis was used to calculate the tumor dose (TD), healthy-injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 months using the European Association for the Study of the Liver criteria. Factors associated with response and toxicity were analyzed using univariate analysis.Results: We assessed a total of 35 patients (five excluded) receiving 55 injections. Mean TD was 322 ± 165Gy and mean HILD was 74 ± 24Gy for a mean ILD of 128 ± 28Gy. All but two lesions responded, with a minimal TD for responding lesions of 158Gy. Six Grade 3-4 permanent liver toxicities were observed. Mean HILD was not associated with liver toxicity (73.2 ± 25.8Gy for patients with liver toxicity and 77.8 ± 16.9Gy for patients without, ns). Only underlying Child-Pugh status (p = 0.0014) and underlying cirrhosis (p = 0.0021) were associated with liver toxicity. Median progression-free survival was 12.7 months and median overall survival (OS) was 28.6 months. Median OS was 52.7 months for patients with Child-Pugh A5 status.Conclusions: When combined with chemotherapy, SIRT is highly effective, with a TD > 158Gy. Tolerance was good except for the few patients with cirrhosis or Child-Pugh status ≥A6, who exhibited some liver toxicity. Prospective studies are warranted to confirm.

International audience; Purpose This study aimed at identifying prior therapy dosimetric parameters using 99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with Y-90-loaded glass microspheres. Methods The dosimetry data of 73 HCC patients were collected prior to the treatment with Y-90-loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated. Results Mean MHT was 35.4 +/- 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the Y-90-microspheres injection (r = -0.56). MHT >= 10% was significantly more frequent for patients with HILD >= 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT >= 10% was also significantly more frequent for patients with a TD >= 205 Gy and a tumor volume (VT) >= 100 cm(3) in patients with initial FRL < 50%. MHT >= 10% was seen in 83.9% for patients with either an HILD >= 88 Gy or a TD >= 205 Gy for tumors larger than 100cm(3) (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT >= 10% was also associated with FRL and the ChildPugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT >= 10%. Conclusion This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.

International audience; PURPOSE: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). The peak incidence of HCC is around 70 years. We aimed to evaluate safety and efficacy of sorafenib in the elderly population. METHODS: We retrospectively reviewed data from patients treated with sorafenib for HCC at our institution. We compared safety and efficacy data across different age groups. RESULTS: Since 2005, 129 patients were treated, 78 (60.5 %) were \textless70 years old and 51 (39.5 %) were ≥70. The frequency of dose reduction was similar between the two groups (48.7 vs. 58.8 %), as was the occurrence of severe toxicities (41.0 vs. 51.0 %) and hospitalization due to toxicity (9.0 vs. 13.7 %). However, asthenia and bleeding were more frequent in the elderly. The higher frequency of bleeding was explained by concomitant antiplatelet treatments, and major asthenia was frequent in PS1 elderly patients. There was a trend toward less frequent interruption of treatment in the younger group (25.6 vs. 39.2 %) and significantly less frequent definitive discontinuation of treatment due to toxicity (24.4 vs. 45.1 %). Median progression-free survival was 5.6 months in both age groups, while median overall survival was 9.6 months in the younger age group and 12.6 months in the older age group. CONCLUSION: Sorafenib showed similar results in terms of safety and efficacy in the elderly and younger HCC populations. Careful baseline evaluation is needed for patient's selection in the elderly population, including discussion about antiplatelet therapy discontinuation and caution in PS1 patients, as well as active management of toxicity.

Selective internal radiation therapy (SIRT) appears to be an interesting treatment possibility for locally-advanced intrahepatic cholangiocarcinoma (ICC), yet the appropriate dosimetry has never been evaluated in this context.We retrospectively studied data from 40 patients treated at our institution withWe assessed a total of 35 patients (five excluded) receiving 55 injections. Mean TD was 322 ± 165Gy and mean HILD was 74 ± 24Gy for a mean ILD of 128 ± 28Gy. All but two lesions responded, with a minimal TD for responding lesions of 158Gy. Six Grade 3-4 permanent liver toxicities were observed. Mean HILD was not associated with liver toxicity (73.2 ± 25.8Gy for patients with liver toxicity and 77.8 ± 16.9Gy for patients without, ns). Only underlying Child-Pugh status (p = 0.0014) and underlying cirrhosis (p = 0.0021) were associated with liver toxicity. Median progression-free survival was 12.7 months and median overall survival (OS) was 28.6 months. Median OS was 52.7 months for patients with Child-Pugh A5 status.When combined with chemotherapy, SIRT is highly effective, with a TD 158Gy. Tolerance was good except for the few patients with cirrhosis or Child-Pugh status ≥A6, who exhibited some liver toxicity. Prospective studies are warranted to confirm.

International audience; BACKGROUND: Pancreatic adenocarcinoma (PA) is diagnosed in most cases at an advanced stage requiring chemotherapy. Folfirinox is the standard first-line treatment. After Folfirinox failure, gemcitabine alone is routinely used as second-line therapy without data supporting this attitude.AIM: Determine the response rate and outcome of patients with advanced PA treated with gemcitabine after Folfirinox failure.METHODS: We retrospectively analyzed all consecutive patients treated with gemcitabine after Folfirinox failure for a locally advanced or metastatic PA between 2009 and 2015. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Response rate, control rate and tolerability were assessed.RESULTS: 96 patients were included (male, 51%; median age, 62; performance status (PS) 0-1, 47%). Median duration on gemcitabine was 2.1 months. The overall disease control rate was 40%. Median OS was 3.7 months (95%CI: 2.5-5.2) and median PFS was 2.1 months (95%CI: 2.0-2.6). Reasons for treatment discontinuation were mostly progression (51%). Age at diagnosis and PS were independently associated with OS in multivariate analysis (HR of 1.86; p=0.0055 and 2.42; p

e15642 Background: Hafnium oxide nanoparticles, NBTXR3, increase the effect of radiotherapy (RT) by enhancing local energy dose deposit within tumor cells, resulting in increased cell death compared to the same dose of RT alone. NBTXR3 efficacy was demonstrated in a phase II/III study in soft tissue sarcoma (NCT02379845) and is currently evaluated in other solid tumors including liver cancers. The use of this radio enhancer is particularly relevant in liver cancer management, a difficult to treat heterogenous population, due to the presence of underlying liver dysfunction. Methods: Phase I/II study of NBTXR3 activated by RT in patients (pts) with HCC (with/without portal vein tumor thrombus) or liver metastasis (mets) [NCT02721056]. The dose escalation part followed a 3+3 design with tested dose levels equivalent to 10%, 15%, 22% and 33% of baseline tumor volume. Patients were treated with a single intralesional injection (ILI) of NBTXR3 followed by Stereotaxic Body RT (SBRT: 45 Gy/3 fractions/5 to 7 days). Determination of recommended dose(s) and early dose limiting toxicities (DLT) were primary endpoints. 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: The 4 levels of ILI dose escalation were finalized (n = 17): 6 pts at 10% (2 SBRT doses tested due to organs constraints), 4 pts at 15% and 22% (due to fiducial displacement and ILI shift) and 3 pts at 33% were included. ILIs were successful and SBRT was delivered as planned with no observed DLT or NBTXR3-related SAE at all levels. Only one grade 1 AE (fatigue) related to NBTXR3 was reported at dose level 33%. No relevant change of CPS or APRI was observed over time. Among 7 evaluable HCC pts the best target lesion responses by mRECIST were: 3 CR and 4 PR and among 5 evaluable mets pts: 2 PR, 1 SD and 2 PD. Conclusions: This study demonstrated the feasibility and good tolerance of the first in class NBTXR3 ILI. These results have supported a protocol amendment adding a higher dose of NBTXR3 (42% of the tumor volume). This innovative approach might constitute a valuable solution for patients with unresectable liver tumors and liver dysfunction. Clinical trial information: NCT02721056.

TPS3619 Background: In the first-line setting, current combination chemotherapy (CT) achieve high objective response rates (ORR) ranging from 40% to 80% and leads to complete resection rate (CRR) of colorectal cancer liver metastasis (CRCLM) in 25% to 50% of patients with initially non-resectable CRLM. However, when patients with CRLM are still not amenable to resection after induction CT, ORRs (~5-30%) and CRRs ( < 10%) obtained with second-line systemic CT are much lower. Combining hepatic arterial infusion (HAI) and systemic (SYS) CT for unresectable CRLM lead to high ORR and the potential of cure in the second-line and further setting. Methods: This multicenter randomized phase II trial conducted in 20 centers in France plans to include 140 patients with CRLM still not amenable to a curative intent-treatment after at least two months of first-line induction SYS CT whatever the tumor response. Patients are randomized (1:1) between intensified biweekly regimen combining HAI oxaliplatin (100 mg/m²) and SYS FOLFIRI (leucovorin 400 mg/m², irinotecan 180 mg/m², and 5-FU 2.4 g/m²over 48 h) plus cetuximab 500 mg/m² or bevacizumab 5 mg/kg (according to RAS status and prior response/tolerance to SYS induction CT) or SYS CT alone according to current guidelines. The primary endpoint is to evaluate and compare the curative-intent (R0-R1) resection (and/or ablation) rate (CRR) of CRLM in both arms. A gain of 20% in CRR is expected (30% in the experimental arm vs. 10% in the control arm; α 5% [two-sided]; β 20%). Stratification factors at randomization are prior adjuvant or SYS induction oxaliplatin-based CT, tumor response to SYS induction CT, and center. Secondary endpoints include progression-free (overall, hepatic and extrahepatic) and overall survival, ORR, relative change in the sum of longest diameters of RECIST target lesions (DoR) and feasibility/tolerability. Since study start, 3 patients have been enrolled to date (planned accrual period: 3 years). Clinical trial information: NCT03164655.

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.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). Due to its peculiar toxicities, improving patient's tolerance may need close follow-up. Nurses can play a crucial role, by driving a patient education program (EP). We aimed to prove that adding EP to usual care (UC) improves patient's care.Since 2011, oncologists referred patients treated by sorafenib to the EP, driven by clinical nurses. It consisted in a visit before first administration, weekly telephone calls and a visit before each oncologist consultation. We retrospectively compared patients followed by the EP to those followed by oncologist in usual care (UC) and patients included in a clinical trial (CT).Since 2005, 129 patients were treated with sorafenib for HCC, 31 (24%) in the EP, 22 (17%) in CT and 76 (59%) with UC. Seventy-one percent of patients in the EP had toxicities identified during a telephone call, which prompted symptomatic measures in 65% of patients, leading to treatment modification before the planned on-site visit in 29% of patients. EP patients required less dose reductions (39% vs. 61% for UC, P=0.04), and median time to first dose reduction was shorter with EP than with UC (25 days vs. 45 days, P=0.036).This study suggests a clinical benefit of EP, with a better toxicity's management of sorafenib, leading to less dose reduction. Different types of EP should be compared prospectively, focusing on quality of life.

Efficacy of radioembolization is derived from radioinduced damage, whereas tumour dosimetry is not considered as yet in prospective clinical trials.This study evaluates the impact of tumour dose (TD), based onWe consecutively included 85 patients with hepatocellular carcinoma treated withResponse rate was 80.3% on lesion-based analysis (n=132), and 77.5% on patient-based analysis. The response rate was only 9.1% for patients with TD205 Gy against 89.7% for those with TD ≥205 Gy (P10This study confirms the highly predictive value of MAA-based TD evaluation for response and OS. TD evaluation and PVT MAA targeting should be further evaluated in ongoing trials, whereas personalized dosimetry should be implemented in new trial designs.

International audience; PURPOSE: Radioembolization of liver cancer with (90)Y-loaded microspheres is increasingly used but data regarding hospital staff exposure are scarce. We evaluated the radiation exposure of medical staff while preparing and injecting (90)Y-loaded glass and resin microspheres especially in view of the increasing use of these products. METHODS: Exposure of the chest and finger of the radiopharmacist, nuclear medicine physician and interventional radiologist during preparation and injection of 78 glass microsphere preparations and 16 resin microsphere preparations was monitored. Electronic dosimeters were used to measure chest exposure and ring dosimeters were used to measure finger exposure. RESULTS: Chest exposure was very low for both products used (\textless10 μSv from preparation and injection). In our experience, finger exposure was significantly lower than the annual limit of 500 mSv for both products. With glass microspheres, the mean finger exposure was 13.7 ± 5.2 μSv/GBq for the radiopharmacist, and initially 17.9 ± 5.4 μSv/GBq for the nuclear medicine physician reducing to 13.97 ± 7.9 μSv/GBq with increasing experience. With resin microspheres, finger exposure was more significant: mean finger exposure for the radiopharmacist was 295.1 ± 271.9 μSv/GBq but with a reduction with increasing experience to 97.5 ± 35.2 μSv/GBq for the six most recent dose preparations. For administration of resin microspheres, the greatest mean finger exposure for the nuclear medicine physician (the most exposed operator) was 235.5 ± 156 μSv/GBq. CONCLUSION: Medical staff performing (90)Y-loaded microsphere radioembolization procedures are exposed to safe levels of radiation. Exposure is lower than that from treatments using (131)I-lipiodol. The lowest finger exposure is from glass microspheres. With resin microspheres finger exposure is acceptable but could be optimized in accordance with the ALARA principle, and especially in view of the increasing use of radioembolization

e16194Background: Hepatocellular carcinoma (HCC) is the most widespread primary liver cancer. Liver metastasis (mets) are even more common with a wide range of malignancies. Management of both live...

TPS195 Background: Outcomes with first-line (1L) chemotherapy for GC/GEJC are limited and new strategies to increase efficacy without added toxicity are needed. Avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, is approved for metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma after progression on platinum therapy (US). In phase 1 studies in advanced GC/GEJC, avelumab showed antitumor activity and a manageable safety profile, including in a subgroup of patients (pts) without progression on 1L chemotherapy who received avelumab as maintenance therapy. JAVELIN Gastric 100 (NCT02625610) is a global, randomized, open-label, phase 3 trial comparing maintenance therapy with avelumab vs continuation of 1L chemotherapy in pts with advanced GC/GEJC who have not progressed after 12 weeks of 1L oxaliplatin/fluoropyrimidine chemotherapy. Methods: Eligible pts have histologically confirmed, unresectable, measurable, locally advanced or metastatic GC/GEJC adenocarcinoma, no prior chemotherapy for advanced disease, no prior therapy targeting T-cell coregulatory proteins, and ECOG PS of 0–1. Pts are not preselected based on PD-L1 expression and pts with HER2+ tumors are excluded. Approximately 466 pts who achieve at least stable disease following 12 weeks of 1L oxaliplatin/fluoropyrimidine chemotherapy will be randomized 1:1 to receive maintenance therapy with either avelumab 10 mg/kg by IV infusion Q2W or continuation of 1L chemotherapy. Maintenance therapy is given until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are overall survival and progression-free survival. Secondary endpoints include best overall response, quality of life measures, safety (NCI-CTCAE v4.03), and tumor biomarkers. Responses are evaluated per RECIST 1.1 and adjudicated by independent review committee. Enrollment is ongoing at sites in North/South America, Asia-Pacific, and Europe. Clinical trial information: NCT02625610.

International audience; Hepatocellular carcinoma (HCC) is the second most common cause of death by cancer in the world. Due to the delayed HCC development in hepatitis C carriers and nonalcoholic fatty liver disease, the incidence of HCC in the elderly is increasing and is becoming a global health issue. Elderly patients with HCC should be assessed through proper oncologic approach, namely, screening tools for frailty (Geriatric-8 or Vulnerable Elders Survey-13) and comprehensive geriatric assessment. This review of the literature supports the same treatment options for elderly patients as for younger patients, in elderly patients selected as fit following proper oncogeriatric assessment. Unfit patients should be managed through a multidisciplinary team involving both oncological and geriatrician professionals. Specific studies and recommendations for HCC in the elderly should be encouraged.

4094 Background: 4 types of gastric NETs are described: type 1 developed on atrophic gastritis (70-80% of cases), type 2 (5-6% of cases) as part of MEN 1, sporadic type 3 (14-25% of cases), and Typ...