397P R-IMMUNE interim analysis: A phase Ib/II study to evaluate safety and efficacy of atezolizumab combined with radio-chemotherapy in a preoperative setting for patients with localized rectal cancer

Background Radiotherapy association with immunotherapy has a strong rationale. This study evaluates this combination before surgery in locally advanced rectal cancer (RC). Methods R-IMMUNE (NCT03127007), a multicentric phase Ib/II prospective trial includes patients with stage II/III RC treated with a preoperative combination of radio-chemotherapy (45-50 Gy/25 fractions, 5FU 225 mg/m2/d, 5d/w from week 1-5) + atezolizumab 1200 mg/infusion (ATZ). The phase Ib had a 3+3 design with a safety period up to surgery and evaluated a single infusion of ATZ at week 3. The phase II, in progress, evaluates 4 infusions of ATZ at weeks 3, 6, 9 and 12. Surgery is planned at week 15. Primary objectives are safety and efficacy based on pathological complete response rate (pCR). Based on a 2-stage Simon design, 36 patients are needed in the phase II to detect a pCR rate increase from 15% to 35% (α = 0.1 and β = 0.1). At least 4 pCRs must be observed among 19 patients treated in the 1st stage to move the 2nd stage. Results This analysis concerns 26 patients treated with the study treatment (median age 66 y-old, 48% male, 88% stage III). Safety was evaluated in 6 patients from phase Ib and 20 from phase II. Overall, 151 AEs were reported and 20 (13%) were grade 3-4 on 9/26 patients, including 2/20 (10%) anastomotic leakage/infections, 4/20 (20%) urinary infections, 1/20 (5%) renal function impairment and 1/20 (5%) immune thrombocytopenia. Three grade 2 immune endocrine disorders were observed. Efficacy was evaluable on 25/26 patients after 1 exclusion for inclusion criteria deviation. Four among 19 patients included in the 1st stage of phase II had a pCR. Overall, 6/25 (24%) pCRs were observed. Conclusions R-IMMUNE interim analysis reveals an acceptable safety profile. Observed pCR rate until now supports the pursuit of the trial. Clinical trial identification NCT03127007

Current practice in approaching controversial diagnostic and therapeutic topics in gastroenteropancreatic neuroendocrine neoplasm management : Belgian multidisciplinary expert discussion based on a modified Delphi method

Background and study aims: Neuroendocrine neoplasms (NENs) are relatively rare, with marked clinical and biological heterogeneity. Consequently, many controversial areas remain in diagnosis and optimal treatment stratification for NEN patients. We wanted to describe current clinical practice regarding controversial NEN topics and stimulate critical thinking and mutual learning among a Belgian multidisciplinary expert panel Patients and methods: A 3-round, Delphi method based project, coordinated by a steering committee (SC), was applied to a predefined multidisciplinary NEN expert panel studying the following controversial topics : factors guiding therapeutic decision making, the use of somatostatin analogues (SSA) in adjuvant setting, the interference between non-radioactive and radioactive SSAs, challenging small intestine neuroendocrine tumor (NET) cases, the approach of the carcinoid syndrome, the role of chemotherapy in well differentiated NET, the relevance of NET G3 and neuroendocrine carcinoma subclassification and the role of imaging techniques in NEN management. Results: A high level of consensus exists regarding the necessary diagnostic work-up, use of imaging techniques and interference between non-radioactive and radioactive SSAs. However, the prognostic impact of tumor functionality might be overrated and adequate diarrhea differential diagnostic work-up in these patients is underused. Significant differences are seen between individual experts and centers regarding treatment preferences both on the treatment modality level, as well as the choice of specific drugs (e.g. chemotherapy regimen). Conclusions: A Delphi-like multi-round expert discussion proves useful to boost critical thinking and discussion among experts of different background, as well as to describe current clinical practice and stimulate mutual learning in the absence of high-level scientific guidance

Pooled analysis of the surgical treatment for colorectal cancer liver metastases.

Liver metastases in colorectal cancer patients decreases the expected 5 year survival rates by a factor close to nine. It is generally accepted that resection of liver metastases should be attempted whenever feasible. This manuscript addresses the optimal therapeutic plan regarding timing of resection of synchronous liver metastases and the use of chemotherapy in combination with resection of synchronous metachronous liver metastases. The aim is to pool all published results in order to attribute a level of evidence to outcomes and identify lacking evidence areas. A systematic search of guidelines, reviews, randomised controlled, observational studies and updating a meta-analysis was performed. Data were extracted and analysed. Data failed to demonstrate an effect of timing of surgery or use of chemotherapy on overall survival. Concomitant resection of liver metastases and the primary tumour may result in lower postoperative morbidity. Systemic peri-operative chemotherapy may improve progression free survival compared to surgery alone

449P Randomized phase II study comparing pathological responses of resected colorectal cancer metastases (CRCM) after bevacizumab (BEV) with FOLFOX or FOLFIRI (BEV-ONCO trial)

Background Pathological response (PR) of resected CRCM after preop treatment is a recognized prognostic factor. Retrospective studies reported that BEV + oxaliplatin-based chemotherapy increased PR compared to irinotecan-based chemotherapy. In this trial, we aim to demonstrate that preop BEV + FOLFOX would increase PR. Methods BEV-ONCO (NCT01858649) is a multicenter prospective randomized (1/1) phase II trial evaluating PR on resected CRCM after 3 to max 6 cycles of mFOLFOX (ARM A) or FOLFIRI (ARM B) + BEV (5mg/kg/2 weeks). Primary endpoint is the major pathological response rate (MPRR) defined as the % of patients presenting CRCMs with a mean tumor regression grade (TRG) <3. Secondary endpoints include DFS, OS, safety, complete PR, R0 resection rate and liver toxicity comprising sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH). 54 pts (27 per arm) are needed to detect a difference (alpha=0.05; beta=0.2) of MPRR proportion of 0.40 between treatment arms (two-sided Fisher's Exact test). Results Among 65 pts included between 06/2013 and 09/2018, 57 pts (28 ARM A / 29 ARM B) have had CRCM resection. Clinical and treatment characteristics were similar in both treatment arms (median age 60 y-old, 51% male, 33% RAS wt, 98% liver CRCM, 75% synchronous, median 2 CRCM/pt, median of 4 chemo cycles and 3 BEV cycles). 11/28 pts presented 1-month postop surgical complications in ARM A (39%, grade 3-4: 17.9%) and 9/29 pts in ARM B (31%, grade 3-4: 6.9%, p=0.58). MPRR was 32% in ARM A and 21% in ARM B (p=0.38). 4 pts presented complete PR (ARM A/B: 14%/0%, p=0.05). No difference between treatment arms was observed for R0 resection (ARM A/B: 89%/93%, p=0.80), SOS (ARM A/B: 54%/38%, p=0.50), NRH (ARM A/B: 21%/17%, p=0.75), DFS (ARM A/B: HR=1.14, 95%CI:0.58-2.21, p=0.71) and OS (ARM A/B: HR=1.38, 95%CI:0.48-4.00, p=0.55). Pts with PR among all CRCM (Max TRG≤3; 44% of pts) had a lower risk of relapse/death (DFS: HR=0.41, 95%CI=0.20-0.82, p=0.01) and death (OS: HR=0.34, 95%CI=0.10-1.11, p=0.07). Conclusions This trial fails to demonstrate any significant difference of PR between BEV with FOLFOX or FOLFIRI but confirms PR as a prognostic factor

Current practice in approaching controversial diagnostic and therapeutic topics in gastroenteropancreatic neuroendocrine neoplasm management. Belgian multidisciplinary expert discussion based on a modified Delphi method.

BACKGROUND AND STUDY AIMS: Neuroendocrine neoplasms (NENs) are relatively rare, with marked clinical and biological heterogeneity. Consequently, many controversial areas remain in diagnosis and optimal treatment stratification for NEN patients. We wanted to describe current clinical practice regarding controversial NEN topics and stimulate critical thinking and mutual learning among a Belgian multidisciplinary expert panel. PATIENTS AND METHODS: A 3-round, Delphi method based project, coordinated by a steering committee (SC), was applied to a predefined multidisciplinary NEN expert panel studying the following controversial topics : factors guiding therapeutic decision making, the use of somatostatin analogues (SSA) in adjuvant setting, the interference between non-radioactive and radioactive SSAs, challenging small intestine neuroendocrine tumor (NET) cases, the approach of the carcinoid syndrome, the role of chemotherapy in well differentiated NET, the relevance of NET G3 and neuroendocrine carcinoma subclassification and the role of imaging techniques in NEN management. RESULTS: A high level of consensus exists regarding the necessary diagnostic work-up, use of imaging techniques and interference between non-radioactive and radioactive SSAs. However, the prognostic impact of tumor functionality might be overrated and adequate diarrhea differential diagnostic work-up in these patients is underused. Significant differences are seen between individual experts and centers regarding treatment preferences both on the treatment modality level, as well as the choice of specific drugs (e.g. chemotherapy regimen). CONCLUSIONS: A Delphi-like multi-round expert discussion proves useful to boost critical thinking and discussion among experts of different background, as well as to describe current clinical practice and stimulate mutual learning in the absence of high-level scientific guidance

Materials characterization of WNxCy, WNx and WCx films for advanced barriers

A ternary WNxCy system was deposited in a thermal ALD (atomic layer deposition) reactor from ASM at 300 degrees C in a process sequence using tungsten hexafluoride (WF6), triethyl borane (TEB) and ammonia (NH3) as precursors. The WC, layers were deposited by a novel ALD process at a process temperature of 250 degrees C. The WNx layers were deposited at 375 degrees C using bis(tert-butylimido)-bis-(dimethylamido)tungsten ((BuN)-Bu-t)(2)(Me2N)(2)W (imido-amido) and NH3 as precursors. WNx grows faster on plasma enhanced chemical vapor deposition (PECVD) oxide than WCx does on chemical oxide. WNxCy grows better on PECVD oxide than on thermal oxide, which is opposite of what is seen for WNx. In the case of the ternary WNxCy system, the scalability towards thinner layers and galvanic corrosion behavior are disadvantages for the incorporation of the layer into Cu interconnects. ALD WC, based barriers have a low resistivity, but galvanic corrosion in a model slurry solution of 15% peroxide (H2O2) is a potential problem. Higher resistivity values are determined for the binary WNx layers. WNx shows a constant composition and density throughout the layer. (C) 2007 Published by Elsevier B.V