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Background: Sunitinib, a multitarget tyrosine kinase inhibitor, showed encouraging antitumor activity and manageable toxicity in patients with advanced midgut neuroendocrine tumors (NETs) in earlier results from phase I and II trials., Patients and Methods: In this phase II trial, patients with a nonresectable grade 1 or 2 midgut progressive NET and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned 1:1 to receive 37.5 mg sunitinib or a placebo, combined with 120 mg lanreotide autogel every 28 days. The planned sample size was 104 patients. The primary outcome was investigator-assessed progression-free survival (PFS)., Results: The study was stopped early because of insufficient patient recruitment. Between January 2013 and December 2016, 44 patients were enrolled and received sunitinib ( n  = 22) or placebo ( n  = 22). The median age was 63.7 years ( Q 1- Q 3 range, 56.6-68.1) and 26 patients (59.1%) were male. The main localization was ileum ( N  = 37, 84.1%) and the majority were grade 2 ( n  = 25, 56.8%). The median follow-up was 36.7 months (95% confidence interval (CI) 34.6-48.2). The median PFS was 9.84 months (95% CI 6.8-23.3) with sunitinib and 11.47 months (95% CI 5.4-15.3) with placebo (hazard ratio (HR) = 0.80, 95% CI 0.41-1.56, p  = 0.51). There was no difference in overall survival between treatment arms (HR = 0.81, (95% CI 0.32-2.01), p  = 0.64). The objective response rate was 9.1% with sunitinib and 0.0% with placebo, and 19 patients (86.4%) had stable disease. Thirty-nine patients (88.6%) completed the baseline QLQ-C30 questionnaire. Baseline health-related quality of life level was similar between treatment arms, except for physical and emotional functioning which were higher ( p  = 0.089) and lower ( p  = 0.023) in the sunitinib arm, respectively. Trends toward longer time until a definitive deterioration in favor of the sunitinib arm were observed for 10 out of 15 dimensions (HRs < 1), with a significant result for financial difficulties (HR = 0.31, (90% CI 0.10-0.94)). Twenty-seven patients (61.4%) had at least one adverse event grade ⩾3 (sunitinib: 72.7%, placebo: 50.0%), with only one patient grade 4 for hypertension and vomiting. Eleven deaths non-related to treatment occurred (sunitinib arm: n  = 5, placebo arm: n  = 6)., Conclusion: Our study does not provide enough evidence to conclude the role of sunitinib in advanced midgut NETs, primarily due to a lower-than-expected number of enrolled patients. While we cannot entirely rule out the efficacy of sunitinib, lanreotide alone may play a significant role., Trial Registration: EudraCT: 2012-001098-94., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: Triplet chemotherapy plus cetuximab showed promising results in phase II trials in unsystematically selected RAS population. We evaluated FOLFIRINOX+cetuximab efficacy as first-line treatment in extended RAS wild-type metastatic colorectal cancer (mCRC) patients., Methods: We retrospectively analyzed patients treated with FOLFIRINOX+cetuximab, using data from clinical trials and real-life practice. Extended mutation analysis was performed when RAS/BRAF status was unavailable. The primary endpoint was progression-free survival (PFS)., Results: Seventy patients (61.4 % male, median age 58.7 years) were analyzed. Eighty percent had left-sided mCRC and 97.1 % had liver metastases. Median PFS and overall survival (OS) were 13.3 and 48.5 months, respectively. The objective response rate was 85.7 %, with 20 % complete response. Primary tumor location did not affect OS and PFS. BRAF wild-type patients (n = 65) had longer PFS (13.3 vs. 6.0 months; p = 0.005) and OS (50.1 vs. 21.2 months; p = 0.007) than BRAF mutated patients (n = 5, including four BRAF V600E ). Median OS was significantly longer in resected patients (n = 39, 55.1 vs. 30.7 months; p = 0.030). Main toxicities were diarrhea (31.4 %) and neutropenia (21.4 %)., Conclusion: FOLFIRINOX+cetuximab provides good PFS, high response rate and prolonged disease control in initially unresectable extended RAS wild-type mCRC. This combination is particularly interesting for selected patients with liver-limited disease eligible to secondary resection., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival., Methods: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group., Results: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P <0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous ( P =0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade ( P =0.977) and location ( P =0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion ( P =0.387)., Conclusion: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited., Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma., Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy., Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023., Main Outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators., Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%)., Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.

Background: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus., Methods: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m 2 docetaxel and 40 mg per m 2 cisplatin on day 1 and 1200 mg per m 2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants., Findings: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths., Interpretation: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies., Funding: GERCOR, Roche., Competing Interests: Declaration of interests Genentech provided atezolizumab for the study. SK reports consultancy, advisory roles, and honoraria from Amgen, BeiGene, Boehringer Ingelheim, Merck, MSD, Pfizer, and Servier; and research funding from Boehringer Ingelheim, Bristol Myers Squibb, Novartis, and Roche. FG reports consultancy for Roche, MSD, Merck Serono, Brenus, Engetix, and Odimma; research grants from AstraZeneca, Roche Genentech, Amgen, XBiotech, and Springworks; and travel or accommodation from Amgen, MSD, Roche, and Servier. CdlF reports honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte Biosciences, Ipsen, Lilly, Merck Serono, MSD, Pierre Fabre Oncologie, Pfizer, Roche, Sanofi-Aventis, and Servier. ES reports consultancy, advisory roles, and honoraria from Amgen, Astellas, BeiGene, Bristol Myers Squibb, Daichi, Merck, MSD, Pierre Fabre, and Servier; and travel or accommodation from Bristol Myers Squibb, MSD, Pierre Fabre, and Servier. DT reports consulting or advisory board fees from AstraZeneca, Sanofi, Amgen, MSD, BMS, Roche, Servier, and Pierre Fabre; and research funding from Pierre Fabre and Sandoz. OB reports honoraria for speaker or advisory roles from Astellas, Merck Serono, Amgen, Servier, Pierre Fabre, Apmonia Therapeutics, Deciphera, and MSD. DV reports consulting fees from Apmonia Therapeutics, Cellprothera, Novartis, Incyte, Veracyte, and Lysarc. FB reports honoraria for speaker or advisory roles from Astellas, Servier, Incyte, Pierre Fabre, BMS, AstraZeneca, Owkin, and MSD. JT reports honoraria for speaker or advisory roles from Astellas, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, BMS, AstraZeneca, Novartis, Takeda, and MSD. MBA reports honoraria for speaker or advisory roles from Bayer, Incyte, Deciphera, Merck, Servier, BMS, Pierre Fabre, and Amgen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Preoperative chemoradiation (CRT) is expected to increase the rate of curative resection and complete histological response. In this trial, we investigated the efficacy of a neoadjuvant CRT regimen in gastric adenocarcinoma (NCT01565109 trial)., Materials and Methods: Patients with stage IB to IIIC gastric adenocarcinoma, endoscopy ultrasound and computed tomography-scan diagnosed, were eligible for this phase II trial. Neoadjuvant treatment consisted of 2 cycles of chemotherapy with DCF (docetaxel, cisplatin, and 5-fluorouracil [5FU]) followed by preoperative CRT with oxaliplatin, continuous 5FU and radiotherapy (45 Gy in 25 fractions of 1.8 Gy, 5 fractions per week for 5 weeks) administered before surgery. R0-resection rate, pathological complete response (pathCR) rate, and survival (progression-free survival [PFS] and overall survival [OS]) were evaluated as primary endpoints., Results: Among 33 patients included, 32 patients (97%) received CRT and 26 (78.8%) were resected (R0 resection for all patients resected). Among resected patients, we report pathCR in 23,1% and pathologic major response (tumor regression grade 2 according to Mandard's classification) in 26,9%. With a median follow-up duration of 5.82 years (range, 0.4 to 9.24 years), the estimated median OS for all 33 patients was not reached; 1-, 3-, and 5-year OS rates were 85%, 61%, and 52%, respectively. Among resected patients, those whose histological response was tumor grade regression (TRG) 1-2 had significantly better OS and PFS rates than those with a TRG 3-4-5 response (p=0.019 and p=0.016, respectively)., Conclusion: Promising results from trials involving preoperative chemoradiation followed by surgery in gastric cancer need to be further evaluated in a phase III trial.

Objective: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma., Design and Methods: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least 1 major criterion (necrolytic migratory erythema [NME] and/or recent-onset diabetes, and/or weight loss ≥ 5 kg) associated with either glucagonemia > 2 × upper limit of normal or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT)., Results: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonoma symptoms at diagnosis were NME (86.8%), weight loss (68.4%), and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75%, and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8), and somatostatin analogs (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival (OS) was 17.3 years. The Ki-67 index > 3% was associated with shorter OS (hazard ratio 5.27, 95% CI [1.11-24.96], P = .036)., Conclusion: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, peptide receptor radionuclide therapy, or liver-directed therapy seems to provide both substantial antitumor and antisecretory efficacies., Competing Interests: Conflict of interest: C.L.: Novartis, Ipsen, AMGEN, and Deciphera; V.H.: AAA, Ipsen, Servier, Pierre Fabre, Deciphera, Amgen, and Merck; G.C.: AAA, Ipsen, Keocyt, and Esteve; T.W.: AAA Pharma, Inc., Ipsen, ESTEVE, MSD, Pierre Fabre, and TERUMO; L.d.M.: AAA, Esteve, Ipsen, and SIRTex. All other authors have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown., Methods: In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR)., Results: 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%-96%) among evaluable patients (n = 32), and 95% (95% CI 70-100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15-23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1-19). Treatment toxicity was manageable, without toxic death., Conclusion: HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DM: Consulting/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Bionest Partners, BMS, Incyte, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Simon-Kutcher & Partners, Servier, Taiho. Honoraria for lectures: Amgen, AstraZeneca, Bayer, BMS, Foundation Medicine, Incyte, Leo Pharma, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier, Veracyte, Viatris. Personal fees for a writing engagement: Medscape. Travel expenses for medical congresses: Amgen, Bayer, BMS, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier, Viatris. BV: none. MF: honoraria for lectures: Novartis. Travel expenses for medical congresses: Ipsen. RG: Consulting/advisory role: Pierre Fabre, BMS, Servier, MSD. Honoraria for lectures: MSD, Servier, Ipsen, BMS, Viatris. Travel expenses for medical congresses: MSD, Ipsen, Roche, Pierre Fabre, Advanced Accelerator Applications (AAA). CC: none. JE: Consulting/advisory role: MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene. Travel expenses for medical congresses: Amgen. Research funding (institutional): BMS, Beigene. MPG: honoraria: Servier, BMS. Travel expenses for medical congresses: AAA, Bayer, Servier, Amgen. LBG: honoraria: AstraZeneca, Servier, KSK, MSD, Bayer, Eisai. DS: travel expenses for medical congresses: Servier, Pierre Fabre. EDB: none. TDB: Consulting/advisory role: Terumo, Boston Scientific. Research funding (institutional): Quantum, Terumo. DG: honoraria for lectures: Merck Serono, Amgen, Sanofi, Servier. PD: Consulting/advisory role: MSD. Honoraria for lectures: AstraZeneca, MSD. Travel expenses for medical congresses: MSD. LL: none. VB: Consulting/advisory role: Merck Serono, Ipsen, Bayer, Eisai, BMS, Roche, AstraZeneca. Honoraria for lectures: Merck Serono, Novartis, Roche, Bayer, MSD, Amgen, Ipsen, AstraZeneca. Travel expenses for medical congresses: Amgen, Merck Serono, Sanofi Genzyme, Bayer, Roche, MSD, Ipsen, AstraZeneca. Research funding (institutional): Merck Serono. MG: none. JPP: none. MD: honoraria for advisory boards or as a presenter in symposium: Merck Serono, MSD, Amgen, Roche, Bayer, Ipsen, Pfizer, Servier, Pierre Fabre, Lilly, Sanofi, Servier, Daiichi Sankyo., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Opinion Statement: Since total neoadjuvant treatment achieves almost 30% pathologic complete response, organ preservation has been increasingly debated for good responders after neoadjuvant treatment for patients diagnosed with rectal cancer. Two organ preservation strategies are available: a watch and wait strategy and a local excision strategy including patients with a near clinical complete response. A major issue is the selection of patients according to the initial tumor staging or the response assessment. Despite modern imaging improvement, identifying complete response remains challenging. A better selection could be possible by radiomics analyses, exploiting numerous image features to feed data characterization algorithms. The subsequent step is to include baseline and/or pre-therapeutic MRI, PET-CT, and CT radiomics added to the patients' clinicopathological data, inside machine learning (ML) prediction models, with predictive or prognostic purposes. These models could be further improved by the addition of new biomarkers such as circulating tumor biomarkers, molecular profiling, or pathological immune biomarkers., (© 2023. The Author(s).)

Background: There is no standard second-line treatment after platinum-etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting., Methods: We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum-etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m 2 , calcium folinate 400 mg/m 2 or levofolinate 200 mg/m 2 , and fluorouracil 400 mg/m 2 bolus then 2400 mg/m 2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857., Findings: Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58-73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0-38·2), 6-month overall survival was 53% (80% CI 43-61) in the FOLFIRI plus bevacizumab group and 60% (51-68) in the FOLFIRI group. Grade 3-4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group., Interpretation: The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma., Funding: French Ministry of Health and Roche SAS., Competing Interests: Declaration of interests TW reports the support from Roche SAS, who provided the bevacizumab for the present study; a grant from Ipsen; fees for consulting or advisory roles from AAA Novartis, IPSEN, Terumo, and Servier; support for attending meetings from Servier and Ipsen; and honoraria for presentations and educational events from Bayer, Ipsen, AAA Novartis, Incyte, and Bristol Myers Squib. AL reports grants from Bayer, Lilly, and Novartis; consulting fees from AAA Novartis, Astellas, Bristol Myers Squib, Incyte, Pierre Fabre, and Servier; honoraria for presentations from AAA, Amgen, Astellas, Bristol Myers Squib, Esteve, Incyte, Ipsen, Leo-pharma, Mylan, Novartis, Pierre Fabre, Roche, Servier, and Viatris; support for attending meetings or travel from Bayer, Boehringer, Ipsen, Mylan, MSD, Novartis, Pierre Fabre, Roche, and Servier; and non-financial interests from AstraZeneca, Bristol Myers Squib, and Incyte. RC reports grants from Ipsen; support for attending meetings or travel from Amgen, Pierre Fabre, and Ipsen; and honoraria for lectures and presentations from Bayer, AAA Novartis, Amgen, Pfizer, Ipsen, and Roche. DM reports consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Incyte, Merck Serono, MSD, Pierre Fabre Oncologie, Roche, Sanofi, Servier, Taiho, and Viatris; honoraria for lectures, presentations, or educational events from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Foundation Medicine, Incyte, Leo Pharma, Medscape, Merck Serono, MSD, Pierre Fabre Oncologie, Roche, Sanofi, Servier, Veracyte, and Viatris; and support for attending meetings or travel from Amgen, Bayer, Bristol Myers Squibb, Merck Serono, MSD, Pierre Fabre Oncologie, Roche, Sanofi, Servier, and Viatris. FDF reports honoraria for lectures, presentations, and educational events for Amgen, AstraZeneca, Bayer, Bristol Myers Squib, Merck, Roche, Servier, Ipsen, Jansen, Astellas, and Pierre Fabre; and support for attending meetings and travel from Servier, Ipsen, Pierre Fabre, and Amgen. VH reports honoraria for lectures and presentations for AAA Novartis, Ipsen, Esteve, Merck, Amgen, and Pierre Fabre; support for attending meetings or travel from Pierre Fabre, Merck, and Amgen; and has a leadership role in other board, society, or committee for GTE and FFCD. VG reports support for attending meetings or travel from Servier. IS reports grants from IPSEN; honoraria for presentations from Novartis; support for attending meetings or travel from Ipsen; and other non-financial interests from Biccodex. EA reports support for attending meetings or travel from Ipsen, MSD, and Servier; honoraria for participation on an advisory board from Bayer, Roche, AstraZeneca, Servier, AAA Novartis, Ipsen, Boston, and Bristol Myers Squibb. CL reports grants from Amgen, Celltrion, Janssen, Gilead, Lilly, and MSD; honoraria for presentations from Amgen, Ipsen, and Pierre Fabre; support for attending meetings from MSD; and participation on an advisory board from AAA Novartis. CL-B reports payment or honoraria for lectures from Ipsen; support for attending meetings from Ipsen; and participation on an advisory board from AAA Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002., (© 2022 Merck Sharp & Dohme LLC and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Intra-arterial hepatic (IAH) treatment has shown promising results in the management of patients with unresectable colorectal liver metastases (CRLM) the prognosis of which is poor. Bevacizumab adjunction to standard chemotherapy has been shown to improve survival of this patient population. This prospective study was conducted to assess the efficacy and safety of IAH bevacizumab combined to systemic chemotherapy after first-line treatment failure in patients with CRLM., Methods: Included patients had dominant or isolated unresectable CRLM progressing after standard first-line treatment for metastases of colorectal cancer. Three patients had less than 30% liver invasion, three patients between 30 and 50%, two more than 50% and data was missing in two patients. An intra-hepatic catheter was implanted surgically or percutaneously. Bevacizumab 7.5 mg/kg was administered once every 3 weeks in combination with capecitabine 2000 mg/m² per day for 2 weeks and oxaliplatin 130 mg/m² or irinotecan 200 mg/m² once every 3 weeks. The primary end-point was the objective response rate., Results: Between June 2013 and February 2015, 10 patients were included. The trial was prematurely closed because of the lack of financial support and poor accrual. The patients had a median of 6 [1-9] cycles of treatment. Partial response was achieved in 2 patients (20%) and a R0 liver metastases resection in one another. All patients died of disease progression. The median overall and progression-free survival rates were respectively 14.0 (95% IC [4.8 - 25.8] and 5.4 months (95% IC [1.6 - 6.2]). Four patients had severe side effects but no toxic death occurred., Conclusion: IAH bevacizumab combined to systemic chemotherapy is feasible and safe in patients with unresectable isolated or dominant CRLM progressing after a first-line systemic treatment. Based on the low number of patients included in our study, our results suggest that this treatment does not increase dramatically the response rate versus an adapted systemic treatment. However, considering the safety data provided in this study, arterial infusion of bevacizumab in adjunction to chemotherapeutic agents could be evaluated in the future., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (&gt;30-50%), and/or bone metastases., Methods: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months., Results: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0-7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1-2 expected toxicities., Conclusions: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed., Trial Registration: NCT02288377 (clinicaltrials.gov)., Competing Interests: Conflict of interest statement Côme Lepage worked as a member of the advisory board for Novartis, personal fees from Novartis, IPSEN, grants from Merck, IPSEN. Thomas Walter worked as a member of advisory boards for AAA, IPSEN, Keocyt and Novartis. Astrid Lièvre reports grants from Bayer Lilly, Merck and Novartis; personal fees from AAA, Amgen, Bayer, Bristol-Myers Squibb, Celgene, HalioDx, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sandoz, Sanofi and Servier; non-financial support from AAA, Amgen, Bayer, Incyte, Ipsen, Merck, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Servier and Integragen. David Tougeron reports grants from Bristol-Myers Squibb and Novartis; personal fees from Amgen, Bayer, Bristol-Myers SquibbIpsen, Novartis, Pierre Fabre, Roche, Sanofi and Servier. Catherine Lombard-Bohas worked as a member of advisory boards for AAA, IPSEN, Keocyt, Novartis. Jean-Louis Legoux worked as a member of an advisory board for Novartis, reports personal fees from Novartis, Pfizer (clinical research), Novartis, Keocyt, Servier (courses, training), Merck, Servier, Keocyt (invitations to national or international congresses). All remaining authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immune checkpoint inhibitors (ICI) have high efficacy in metastatic colorectal cancer (mCRC) with microsatellite instability (MSI) but not in microsatellite stable (MSS) tumour due to the low tumour mutational burden. Selective internal radiation therapy (SIRT) could enhance neoantigen production thus triggering systemic anti-tumoral immune response (abscopal effect). In addition, Oxalipatin can induce immunogenic cell death and Bevacizumab can decrease the exhaustion of tumour infiltrating lymphocyte. In combination, these treatments could act synergistically to sensitize MSS mCRCs to ICI SIRTCI is a prospective, multicentre, open-label, phase II, non-comparative single-arm study evaluating the efficacy and safety of SIRT plus Xelox, Bevacizumab and Atezolizumab (anti-programmed death-ligand 1) in patients with liver-dominant MSS mCRC. The primary objective is progression-free survival at 9 months. The main inclusion criteria are patients with MSS mCRC with liver-dominant disease, initially unresectable disease and with no prior oncologic treatment for metastatic disease. The trial started in November 2020 and has included 10 out of the 52 planned patients., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Hepatic arterial infusion (HAI) of chemotherapy is an option for the treatment of patients with liver metastases from colorectal cancer (LMCRC). Though HAI with oxaliplatin (HAI-Ox) is generally used, intravenous (IV) 5-fluoro-uracil (5FU)-oxaliplatin-irinotecan HAI (HAI-Folfirinox) is feasible and leads to curative-intent surgery in 30% of pretreated patients. We compared the efficacy and safety of HAI-Ox and HAI-Folfirinox., Methods: Patients who underwent HAI chemotherapy for LMCRC were retrospectively included from 2008 to 2019 from six French expert centers., Results: Data were collected from 273 previously treated patients with LMCRC. Patients received HAI-Folfirinox ( n = 52) or HAI-Ox ( n = 221) combined with IV chemotherapy. The objective response rate (ORR) was 43.2% in patients with HAI-Folfirinox and 45.9% (ns) in patients with HAI-Ox. Median overall survival (OS) was 17 months (95% CI: 15-32.3) with HAI-Folfirinox and 26.2 months (95% CI: 19.4-34.4; p = 0.1) with HAI-Ox. Median progression-free survival (PFS) was 7.9 months (95% CI: 4.9-10.3) with HAI-Folfirinox and 6.4 months (95% CI: 6.0-7.7; p = 0.6) with HAI-Ox. The secondary liver resection rate was 35.6% with HAI-Folfirinox and 16.7% with HAI-Ox ( p = 0.007). Grade 2 and above toxicities were significantly more frequent with HAI-Folfirinox. In the global population, only 2 factors were prognostic for OS in multivariable analyses: liver-only disease [hazard ratio (HR): 0.4; 95% CI 0.20-0.83; p = 0.013] and local complications of the catheter (HR: 3.8; 95% CI 1.6-9.0; p = 0.002)., Conclusion: Hepatic arterial infusion results in high response rates, secondary resections, and long survival in pretreated patients with LMCRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Randrian, Pernot, Sionneau, Smith, Lim, Touchefeu, Gallois, Turpin, Javed, Guimbaud, Rivera, Karoui, Auclin and Taieb.)

Introduction: Approval of sunitinib and everolimus for the treatment of progressive, unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors (pNETs) was obtained in France in 2011 and 2012, respectively. OPALINE was set up as an observational study to evaluate the efficacy of sunitinib and everolimus compared to usual pNET treatments of chemotherapies and somatostatin analogues that had been previously recommended by the health authorities., Methods: The OPALINE study assessed the efficacy of everolimus and sunitinib in terms of survival, disease progression and tolerance. Patients (N = 144) were enrolled from May 2015 to September 2017, and their disease characteristics were analyzed from diagnosis to 2 years post-enrollment., Results: At inclusion most patients had comorbidities, and about 95% presented metastases. Patients received on average 3.2 lines of treatment from diagnosis to inclusion and two lines throughout the 2-year follow-up. Seventy-nine patients (59.0%) received at least one targeted therapy (TT) during their care path. For these patients, the overall survival (OS) was approximatively 176.5 months (95% CI: 97.2-not evaluable), with a 2-year survival rate estimated at 93.6% (SD 2.6%). Similar survival rates were observed whether the TTs were prescribed sooner or later in the treatment path. The main reasons for discontinuation of TTs were disease progression (54 patients) and adverse events (26 patients). Most patients receiving TTs did not change their dose during the follow-up reflecting the good treatment tolerability over time. No new safety alert was reported for everolimus and sunitinib during this study., Conclusion: Given their good tolerance and positive impact on estimated OS, the two TTs have an important role to play in the care path of patients with pNETs., Gov National Clinical Trial Number: NCT02264665., (© 2022. The Author(s).)

Background: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study., Methods: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m 2 on day 1, leucovorin 400 mg/m 2 on day 1, and fluorouracil 400 mg/m 2 bolus on day 1 followed by a continuous infusion of 1200 mg/m 2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m 2 on day 1, leucovorin 400 mg/m 2 on day 1, and fluorouracil 400 mg/m 2 bolus on day 1 followed by a continuous infusion of 1200 mg/m 2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m 2 , then 250 mg/m 2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients., Findings: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy., Interpretation: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer., Funding: MSD., Competing Interests: Declaration of Interests LAD Jr reports membership on the board of directors of Personal Genome Diagnostics and Jounce Therapeutics; honoraria for consulting and advisory role to Personal Genome Diagnostics, 4Paws, and Neophore; uncompensated advisory and consulting role for Merck Sharp & Dohme; clinical trial funding paid to institution from Merck Sharp & Dohme; and patents for circulating tumour DNA analyses and mismatch repair deficiency for diagnosis and therapy with checkpoint blockade from Johns Hopkins University, the latter licensed to Personal Genome Diagnostics and Qiagen (some licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD Jr); and equity in 4Paws, Personal Genome Diagnostics, Jounce Therapeutics, Thrive Earlier Detection and Neophore; his spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. K-KS reports honoraria including compensation for travel, accommodation, and expenses from Bayer, Bristol Myers Squibb, Guardant Health, Daiichi-Sankyo, Innovent Biologics, Merck KGaA, Merck Sharp & Dohme, Mirati Therapeutics, Roche, and Servier; and Institutional Funding for Research from Adaptimmune Therapeutics, AstraZeneca, Merck KGaA, Merck Sharp & Dohme, and Roche. T-WK reports clinical trial funding paid to institution from Merck Sharp & Dohme and Merck Serono. BVJ, DS, MB, and PG report clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme. LHJ reports research funding to the institution from Merck Sharp & Dohme, 2cureX, Incyte, and Bristol Myers Squibb. CP reports research funding to the institution from Merck Sharp & Dohme; and a consulting and advisory role to Bayer, Nordic Pharma, and Servier. RG-C reports clinical trial funding paid to institution from Merck Sharp & Dohme, Bristol Myers Squibb, Ipsen, Roche, Servier, Novartis, Pfizer, Merck, Bayer, and Pharma Mar; and honoraria from Roche, Sanofi Aventis, Servier, Novartis, Pfizer, Merck, Bayer, Pharma Mar, AAA, Advandz Pharma, Midatech Pharma, and Pierre Fabre. CdlF reports clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme; a consulting and advisory role for Merck Sharp & Dohme (ESMO 2019). FR reports clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, Servier, and Lilly; a consulting and advisory role for Roche, Merck-Serono, Amgen, Pierre Fabre, Sanofi-Aventis, Bayer, Servier, Lilly, AstraZeneca, and Bristol Myers Squibb; honoraria from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, Servier, Lilly, AstraZeneca, Pfizer, and Bristol Myers Squibb; and non-financial support from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, and Servier. Exrts clinical trial funding paid to institution from Merck Sharp & Dohme and Sanofi; honoraria from Amgen, Sanofi, Servier, Merck Sharp & Dohme, Pierre Fabre, and Hoffman La Roche; and non-financial support from Amgen, Sanofi, Merck Sharp & Dohme, and Hoffman La Roche. DTL serves on advisory boards for Merck, Bristol Myers Squibb, and Janssen; has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, Nouscom, and AbbVie; has received speaking honoraria from Merck; and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. The terms of these arrangements are being managed by Johns Hopkins. TY reports grants from Merck Sharp & Dohme for the submitted work; and grants from Ono, Sanofi, Daiichi Sankyo, Chugai, Parexel International, Taiho, Amgen, and Sumitomo Dainippon, outside the submitted work; WYZ, DF, and PM are employees of Merck Sharp & Dohme, a subsidiary of Merck, and hold stock in Merck. TA reports honoraria from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Chugai, Clovis, Gritstone Oncology, GSK, Haliodx, Kaleido Biosciences, Merck, Pierre Fabre, Roche/Ventana, Sanofi, Transgene, Seagen, and Servier; and compensation for travel, accommodation, and expenses from Roche/Genentech, Merck Sharp & Dohme, and Bristol Myers Squibb., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy., Aim: The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM., Materials and Methods: Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and <10 mm, ECOG performance status 0 or 1., Endpoint: The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life., Conclusion: This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753)., Competing Interests: Conflict of interest PRODIGE 49 – Oscar Trial is funded in part by Amen Simon Pernot has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Astra Zeneca, Servier, Pierre Fabre, and Amgen David Tougeron has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, BMS, Astra Zeneca, Servier, Pierre Fabre, Sandoz and Amgen Claire Gallois has received honoraria as a speaker and/or in an advisory role from Sanofi, Servier Faiza Khemissa has received honoraria as a speaker and/or in an advisory role from Sanofi, Bayer Michel Ducreux has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, BMS, Astra Zeneca, Servier, Pierre Fabre, Sandoz and Amgen Julien Taieb has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, BMS, Astra Zeneca, Servier, Pierre Fabre, Sandoz and Amgen Other authors didn't declare any conflict of interest., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Squamous cell carcinoma of the anus (SCCA) is a rare disease often diagnosed at a localised stage. For locally advanced recurrence or metastatic disease, DCF (docetaxel, cisplatin, 5-fluorouracil) demonstrated high efficacy and became one of the standard regimens. However, there is no standard of care in the second line., Patients and Methods: In the Epitopes-HPV01 and Epitopes-HPV02 prospective trials, 115 patients with advanced SCCA were treated with a DCF regimen in the first line. In these studies, second-line data were registered per protocol., Results: After a median follow-up of >40 months, at progression, 73 patients received a second-line (L2) treatment. In this L2 population, median overall survival (mOS) was 13.5 months (95%CI 9.4-19.8), and median progression-free survival (mPFS) was 5.7 months (3.4-7.3) in L2. Fourteen patients presented an oligometastatic progression and were treated with an ablative treatment (surgery or radiotherapy); mOS was 48.3 months (NE-NE), and mPFS was 31.3 months (23.2-NE). Fifty-nine patients received a systemic treatment (chemotherapy or immunotherapy); mOS was 11 months (8.4-15.4) and mPFS was 4.9 months (3.3-7). The most frequent chemotherapy regimens were the reintroduction of DCF, paclitaxel, FOLFIRI and mitomycin plus fluoropyrimidine. No significant difference was observed between regimens (p = 0.26). Six patients received anti-PD1/L1-based immunotherapy., Conclusion: Second-line treatments are effective in patients with SCCA. Ablative treatment is feasible and is probably the best option for patients with oligometastatic progression. If this is not possible, systemic therapy by an anti-PD1/L1 immunotherapy or chemotherapy can be recommended. Reintroduction of DCF, paclitaxel, FOLFIRI or mitomycin-C plus fluoropyrimidine are possible options., Competing Interests: Conflict of interest statement The authors declare no conflict of interest associated with this manuscript., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Vasoactive intestinal peptide-secreting tumor (VIPoma) is a very rare, life-threatening, functioning pancreatic neuroendocrine tumor (pNET). The efficacy of antitumor therapies against functioning symptoms and tumor burden have been poorly described in VIPoma., Objective: Describe the impact of treatments on the secretory syndrome, tumor burden and survival in patients with VIPoma., Methods: We retrospectively reviewed the records of patients with VIPoma treated in seven French expert centers between 1990 and 2016. Diagnostic of VIPoma was reassessed using strict criteria. We evaluated the antisecretory efficacy (>50 % decrease of daily bowel movements), and antitumor efficacy (RECIST 1.1) of all treatments received., Results: Twenty-two patients were included. pNETs were mostly metastatic (77 %) and classified as grade 2 (83 %). Median follow-up was 78.2 months. Surgical excision of nonmetastatic VIPoma effectively controlled the secretory syndrome. Although 4/5 patients had metastatic recurrences, all patients were alive after median post-operative follow-up of 171 months. Among the 87 treatments received for metastatic VIPoma, curative-intent surgery (n = 14), somatostatin analogs alone (n = 11), chemotherapy (n = 23), transarterial liver embolization (TALE) (n = 14), everolimus (n = 10) and sunitinib (n = 7) achieved, respectively, 100 %, 67 %, 83 %, 50 %, 20 % and 100 % antisecretory efficacy. The 5-year OS rate was 63.6 %, with pejorative impact of higher Ki-67 index (P = 0.045) and higher plasma VIP concentration (P = 0.025)., Conclusions: Surgical resection of localized VIPoma is effective but rarely curative. For metastatic VIPoma, curative-intent surgery, chemotherapy and sunitinib are the therapeutic options that best combined antitumor and antisecretory efficacies., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

The pathological nodal stage, determination of which requires examination of ≥ 12 lymph nodes, is one of the main prognostic factors in rectal cancer. Neoadjuvant chemoradiotherapy (CRT) may reduce the number of both lymph nodes retrieved and positive lymph nodes. Induction chemotherapy before CRT aimed at reducing the rate of distant metastases. However, the impact of this new treatment on number of lymph nodes retrieved and positive lymph nodes is unknown. This study was performed to evaluate the effects of neoadjuvant chemotherapy on lymph nodes in locally advanced rectal cancer treated by CRT. We retrospectively included patients with T2 - 4 Nx M0 rectal cancer and compared those receiving neoadjuvant chemotherapy plus CRT with those receiving CRT alone. From 2012 to 2019, 85 patients were treated with neoadjuvant chemotherapy + CRT and 189 with CRT alone. The number of lymph nodes retrieved (19 vs. 17, respectively, P = 0.434), the rate of specimens with ≥ 12 lymph nodes (92% vs. 88%, respectively, P = 0.397), and the median number of positive lymph nodes (1 vs. 2, respectively, P = 0.878) were similar between the two groups. However, the rate of pN0 was higher after neoadjuvant chemotherapy + CRT compared to CRT (75% vs. 62%, respectively, P = 0.030). Neoadjuvant chemotherapy before CRT for locally advanced rectal cancer did not modify the number of lymph nodes retrieved or the number of positive lymph nodes compared to CRT alone. However, it significantly increased the rate of tumors without any positive lymph nodes (ypN0)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: The COVID-19 pandemic has been associated with substantial reduction in screening, case identification, and hospital referrals among patients with cancer. However, no study has quantitatively examined the implications of this correlation for cancer patient management., Objective: To evaluate the association of the COVID-19 pandemic lockdown with the tumor burden of patients who were diagnosed with metastatic colorectal cancer (mCRC) before vs after lockdown., Design, Setting, and Participants: This cohort study analyzed participants in the screening procedure of the PANIRINOX (Phase II Randomized Study Comparing FOLFIRINOX + Panitumumab vs FOLFOX + Panitumumab in Metastatic Colorectal Cancer Patients Stratified by RAS Status from Circulating DNA Analysis) phase 2 randomized clinical trial. These newly diagnosed patients received care at 1 of 18 different clinical centers in France and were recruited before or after the lockdown was enacted in France in the spring of 2020. Patients underwent a blood-sampling screening procedure to identify their RAS and BRAF tumor status., Exposures: mCRC., Main Outcomes and Measures: Circulating tumor DNA (ctDNA) analysis was used to identify RAS and BRAF status. Tumor burden was evaluated by the total plasma ctDNA concentration. The median ctDNA concentration was compared in patients who underwent screening before (November 11, 2019, to March 9, 2020) vs after (May 14 to September 3, 2020) lockdown and in patients who were included from the start of the PANIRINOX study., Results: A total of 80 patients were included, of whom 40 underwent screening before and 40 others underwent screening after the first COVID-19 lockdown in France. These patients included 48 men (60.0%) and 32 women (40.0%) and had a median (range) age of 62 (37-77) years. The median ctDNA concentration was statistically higher in patients who were newly diagnosed after lockdown compared with those who were diagnosed before lockdown (119.2 ng/mL vs 17.3 ng/mL; P < .001). Patients with mCRC and high ctDNA concentration had lower median survival compared with those with lower concentration (14.7 [95% CI, 8.8-18.0] months vs 20.0 [95% CI, 14.1-32.0] months). This finding points to the potential adverse consequences of the COVID-19 pandemic and related lockdown., Conclusions and Relevance: This cohort study found that tumor burden differed between patients who received an mCRC diagnosis before vs after the first COVID-19 lockdown in France. The findings of this study suggest that CRC is a major area for intervention to minimize pandemic-associated delays in screening, diagnosis, and treatment.

Background: Neoadjuvant treatment (NAT) is debated for borderline resectable pancreatic cancer (BRPC). This retrospective study assessed the impact of NAT on R0 rate and survival for BRPC patients in comparison with upfront surgery (US)., Material and Methods: Between 2010 and 2017 patient records for all consecutive patients treated for BRPC according to NCCN 2017 were reviewed. The endpoints analysed were R0 rate, recurrence-free-survival (RFS) and overall survival (OS)., Results: Seventy-nine patients were included: 63 (79.7%) patients received NAT and 16 (20.3%) were upfront operated. NAT consisted in FOLFIRINOX (median cycles: 5, range 4-8) followed by chemoradiation ( n  = 55, 87.3%, median dose: 54 Gy). Thirty-nine (61.9%) patients had resection. R0 rate was higher in the NAT group considering a margin clearance of 0 mm (94.9%) or 1 mm (89.7%) compared to the US group (68.8% and 43.8% respectively). In the whole population, median RFS was 12.6 [95%CI: 10.5-22.1] in the NAT group vs 7.7 [95%CI: 4.4-14] months in the US group ( p  < 0.01). Median OS was 29.0 [95%CI: 23.5-63.1] and 27.2 [95%CI: 11.6-38.8] months in the NAT and US groups respectively ( p  = 0.06). In operated patients the NAT group achieved better RFS and OS than the US group ( p  < 0.01 for both). In multivariate analysis NAT, surgical resection and age <65 ( p  < 0.01 for both) were prognostic of RFS. NAT, surgical resection and adjuvant chemotherapy were prognostic of OS ( p  < 0.05 for all). In operated patients ( n  = 55) multivariate analysis showed that N1 status was associated with decreased RFS; age < 65 and NAT were associated with a longer RFS. Receiving a NAT, an adjuvant chemotherapy and achieving a ypT0-1N0 status were associated with better OS. NAT was well tolerated with 14.3% grade ≥ 3 toxicities., Conclusion: NAT permitted a high R0 rate with a 0- or 1-mm clearance margin and was associated with better RFS and OS for patients with BRPC.

Aim: Treatment strategies in locally recurrent rectal cancer (LRRC) are complex and need to be balanced against previous treatments received for the primary rectal cancer. Radiotherapy is an important component of treatment in LRRC. However, there is little high-quality evidence on the role of reirradiation in this cohort. Therefore, the aim of this trial is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC., Method: GRECCAR 15 is a prospective, multicentre, open-label, outcome assessor-blinded, superiority randomized controlled phase III clinical trial comparing neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone in patients with LRRC previously irradiated for the primary cancer. Adult patients (>18 years old) with a histologically proven resectable LRRC, who have previously received pelvic radiotherapy for their primary rectal cancer at a dose of 25-50.4 Gy, and an Eastern Cooperative Oncology Group performance status of <2 will be eligible to participate. The pelvic reirradiation will consist of conformational intensity-modulated external irradiation, delivering a dose of 30.6 Gy with concomitant chemotherapy using capecitabine. The primary outcome of this trial is the R0 resection rate. Overall, GRECCAR 15 aims to recruit 186 patients to detect an absolute difference of 20% in the R0 resection rate with 80% power and 5% two-sided significance level., Conclusion: The GRECCAR 15 trial is the first, definitive, phase III trial to investigate reirradiation in LRRC. The results of this trial will inform definitively the neoadjuvant treatment strategy in previously irradiated patients and assess whether there is any associated benefit of reirradiation in combination with induction chemotherapy in improving R0 resection rates., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Background: In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here., Methods: KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed., Findings: Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001)., Interpretation: Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA., Competing Interests: Declaration of interests TA reports consulting or advisory roles, or both, and received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai, Clovis Oncology, GlaxoSmithKline, Gritstone Oncology, HalioDx, Pierre Fabre, Roche/Ventana, Sanofi, Servier, Tesaro and Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA (MSD); travel, accommodations, and expenses from Roche/Ventana, Bristol Myers Squibb, and MSD; speaker bureau fees from Bristol Myers Squibb and Servier; and research funding from MSD. TA also reports participation in the scientific committee of the ARCAD foundation and GERCOR group as non-renumerated activities. MA is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA, and is a shareholder in Merck & Co, Kenilworth, NJ, USA. JMN is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ USA, and may own stock or hold stock options, or both, in the Company. K-KS reports honoraria from Bristol Myers Squibb, Guardant Health, Innovent Biologics, Merck KGaA, Roche, and Servier; consulting or advisory roles, or both, for Roche; research grants or funding, or both, from Amgen, Bristol Myers Squibb, Gilead, Merck KGaA, Roche, and MSD; and travel, accommodations, and expenses from Merck KGaA, Innovent Biologics, and MSD. TWK reports research grants or funding, or both, from Merck Serono, AstraZeneca, and Pfizer. BVJ reports research grants or funding, or both, from MSD. LHJ reports research grants or funding, or both, to his institution from 2cureX, Incyte, Bristol Myers Squibb, and MSD. CJAP reports advisory roles for Nordic Pharma. DS declares no competing interests. RG-C has provided scientific advice, attended speakers bureau, or received honoraria from AAA, Advanz Pharma, Bayer, Bristol Myers Squibb, HMP, Ipsen, Merck & Co, Midatech Pharma, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Sanofi, Servier, and MSD; and has received support to his institution for the conduct of clinical trials or for molecular diagnostic platforms from ARMO Biosciences, AstraZeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics, Boston Biomedicals, Merck & Co, Amgen, Sanofi, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, Pharmamar, and MSD. RG-C also reports financial support from Pfizer and Bristol Myers Squibb to an investigator-initiated trial evaluating axitinib in neuroendocrine tumours and nivolumab in neuroendocrine carcinomas. RG-C also reports being a member of the Executive Committee of the Spanish Neuroendocrine Tumor Cooperative Group (GETNE), the Executive Committee of the European Society of Neuroendocrine Tumors (ENETS), the Scientific Advisory Group for Oncology (SAG-O) of the European Medicines Agency (EMA; 2008–17), EORTC, ASCO, ESMO, SEOM, TTD, GEMCAD; and is a global PI of a clinical trial of Axitinib (Pfizer) in neuroendocrine tumours and a clinical trial of nivolumab (Bristol Myers Squibb) and chemotherapy in neuroendocrine carcinomas. IS reports advisory or consultancy, or both, roles for Ipsen, Pfizer, Syrtex, Amgen, and Pharmamar; and speaker bureau fees from AAA, Sanofi, and Novartis. CDLF reports advisory or consultancy, or both, roles for Roche, Pierre Fabre, Oncologie, Eisai, Bayer, and MSD; and travel, accommodations, and expenses from Amgen, Eisai, Bristol Myers Squibb, and Roche. FR reports honoraria; advisory or consultancy roles, or both; research grants or funding, or both; travel, accommodations, and expenses from Roche, Merck-Serono, Sanofi, Bristol Myers Squibb, Servier, Lilly, Amgen, Bayer, Celgene, and MSD. EE reports personal financial interests, honoraria, advisory roles, travel grants, and research grants from Hoffman-La Roche, Sanofi, Aventis, Amgen, Merck Serono, Servier, Array Pharmaceuticals, Bristol Myers Squibb, and MSD; and institutional financial interests and honoraria from Hoffman-La Roche, Sanofi Aventis, Amgen, Merck Serono, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre Fabre, Novartis, Bristol Myers Squibb, GlaxoSmithKline, MedImmune, and MSD. LAD is a member of the board of directors of Personal Genome Diagnostics and Jounce Therapeutics. LAD is a compensated consultant to PGDx, 4Paws (PetDx), Innovatus CP, Se'er, Kinnate, and Neophore. LAD is an uncompensated consultant to Merck & Co. LAD has received research support for clinical trials from Merck & Co. LAD is an inventor of multiple licensed patents related to technology for circulating tumour DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD. LAD holds equity in Personal Genome Diagnostics, Jounce Therapeutics, Thrive Earlier Detection, Se'er, Kinnate and Neophore. LAD's spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. TY reports research funding from Novartis Pharma, MSD, Sumitomo Dainippon Pharma, Chugai Pharmaceutical, Sanofi, Daichi Sankyo, Parexel International, Ono Pharmaceutical, and GlaxoSmithKline. EVC reports advisory board roles for Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Incyte, Ipsen, Lilly, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and MSD; and research funding from Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck KGaA, Novartis, Roche, Servier, and MSD. PY is an employee of MSD China Holding. MF is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ USA, who may own stock or hold stock options, or both in the Company. DTL reports advisory board roles for MSD and Bristol Myers Squibb; research funding from MSD, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom; honoraria from MSD; and is an inventor of licensed intellectual property from Johns Hopkins University., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC)., Methods: EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression., Results: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients., Conclusions: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment., (© 2020 The British Pharmacological Society.)

Background: The care management of colorectal cancers has evolved, particularly since the implementation of multidisciplinary team meetings (MDTm). The aim of this study was to identify factors associated with the non-presentation of colon cancer patients in MDTm (no-MDTm) and to assess the association between no-MDTm and the diagnostic and therapeutic care management, in two areas in France, in 2010., Methods: Patients over 18 years diagnosed for invasive colon cancer in Gironde and Tarn during 2010 were included from the cancer registries of these two departments. We used five indicators to evaluate the care management of colon cancer patients (about diagnosis, treatment and selection of patients for chemotherapy)., Results: No-MDTm patients were more likely to die early after diagnosis (OR=2.94, 95% CI=[1.52-5.66]). Elderly patients and those living in more disadvantaged areas were less often presented in MDTm (OR ≥85years =2.10, 95% CI=[1.06-4.18]; OR EDI Q4-Q5 =1.96, 95% CI=[1.23-3.14]). After adjusting for patient-related variables (age, comorbidities, deprivation) and tumor (stage at diagnosis), we found that thoracic CT scan was less often performed among no-MDTm patients (OR=0.40, 95% CI=[0.24-0.65]). There was no association between the absence of MDTm and the therapeutic care management indicators., Conclusion: In conclusion, therapeutic care management was not associated with the absence of MDTm but with patient and tumor characteristics, including age, comorbidities and level of deprivation, that influence the non-presentation in MDTm., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: A surveillance program was performed in colorectal cancer (CRC) patients after surgery, to diagnose asymptomatic recurrence., Aims: To assess whether 18-FDG positron emission tomography/CT (PET/CT) improved the detection of recurrence during a 3-year follow-up., Methods: A multicentre, two-arm randomised prospective trial comparing different 36-month follow-up strategies. Complete colonoscopy was performed at baseline and after 3 years and clinical exams with imaging every 3 months. The conventional arm (A) received carcinoembryonic antigen, liver echography, and alternated between lung radiography and computed tomography (CT) scans. The experimental arm (B) received PET/CT., Results: A total of 365 patients with colon (79.4%) or rectal cancer (20.6%), stages II (48.2%) or III (50.8%), were enroled in this study. At 36 months, intention-to-treat analysis revealed recurrence in 31 (17.2%) patients in arm A and 47 (25.4%) in arm B (p = 0.063). At 3 years, 7 of 31 relapses (22.5%) in arm A were surgically treated with curative intent, compared to 17 of 47 (36.2%) in arm B (p = 0.25). The rates of recurrence and new cancers were higher in arm B than arm A (p = 0.038)., Conclusions: PET/CT follow-up every 6 months did not increase the rate of recurrence at 3 years or the rate of surgically treated recurrence compared with conventional follow-up., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown., Methods: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival., Results: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group., Conclusions: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Regorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities., Objectives: to assess the efficacy and safety of regorafenib at it's approved dose in the older population., Patients and Methods: This multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off)., Results: Forty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3-4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy., Conclusion: Treatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although elderly patients are the first concerned by colorectal cancer (CRC), they are underrepresented in clinical trials. The real-world CASSIOPEE study was thus conducted in elderly patients treated for metastatic CRC (mCRC)., Methods: This French prospective, multicenter, noninterventional study aimed to estimate 1-year progression-free survival (PFS) and overall survival (OS), and describe treatments, patient autonomy (Instrumental Activities of Daily Living; Balducci scale), and safety over 24 months, in patients older than 75 with mCRC, starting first-line bevacizumab plus chemotherapy (NCT01555762)., Results: From 2012 to 2014, 402 patients were included (safety population: n = 383, efficacy population: n = 358). Patient characteristics were as follows: mean age, 81 ± 4 years (<80 years, 46%; 80-85 years, 44%; >85 years, 10%); men, 52%; colon primary tumor, 80%; main metastatic site, liver 66%; Eastern Cooperative Oncology Group performance 0-1, 81%. Median PFS was 9.1 months (95% confidence interval [CI]: 8.3-10.2). It was superior for patients ≤85 years (<80 years: 9.3 months; 80-85 years: 9.5 months) compared with patients >85 years (8.3 months). Median OS was 19.0 months (95% CI, 16.5-21.5) and decreased in the 2 oldest groups (20.6, 17.8, and 13.0 months). Autonomy assessments decreased over time leading to nonconclusive results. Twenty-six percent of patients experienced serious adverse events (SAEs): 7% bevacizumab-related SAEs, and 6% bevacizumab-targeted SAEs. Two fatal bevacizumab-related adverse events were reported (hemorrhagic stroke and intestinal ischemia)., Conclusions: This large French real-world study showed that medically fit older patients with mCRC could have a benefit/risk balance similar to that of younger patients when treated with first-line bevacizumab plus chemotherapy. Improvements in geriatric assessments are needed to better define this population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The first long-acting release (LAR) formulation of octreotide was marketed in France in the late 1990s. An injectable formulation of Sandostatin LAR ® (Novartis SAS) with a new diluent has been developed to facilitate its preparation and administration and to improve its use in practice., Methods: We conducted an observational, cross-sectional and multicenter study in France whose main outcome was to compare nurses' satisfaction with the preparation and administration of both previous and new formulations of octreotide LAR. Secondary outcomes included assessment of patient satisfaction (quality of life and pain felt during the injection) and product tolerance. Data were collected at two time points (one for the first formulation group and one for the second formulation group) through paper questionnaires administered to physicians, patients and nurses including a visual analog scale (VAS) from 0 (unsatisfied) to 10 (very satisfied)., Results: Results showed that overall nurse satisfaction improved from 5.3 (95% CI 4.9-5.8) with the previous formulation to 7.5 (95% CI 7-7.9) with the new formulation (p < 0.0001). Regarding secondary outcomes, the simplicity of the injection increased (84% for the previous formulation and 94% for the new formulation) and the purge problem disappeared (36% for the previous formulation and 4% for the new formulation)., Conclusion: The improvement due to the new formulation of Sandostatin LAR ® was reported in terms of handling, ease of use and overall nurse satisfaction. The new formulation greatly reduced treatment administration problems associated with the previous formulation, while maintaining low injection site pain and an equivalent safety profile in both indications.

Background: Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection., Methods: In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session., Results: Fifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3)., Conclusions: Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal., Clinical Trial Registration: NCT01839877.

Background: GRECCAR 2 was the first multicentre, randomised trial to compare local excision with total mesorectal excision in downstaged low rectal cancer. Encouraging oncological results were noted at 3 years' follow-up but needed to be corroborated with longer follow-up. In this study, we aimed to report the 5-year oncological outcomes, including local recurrence, metastatic disease, and survival., Methods: Patients age 18 years and older with T2T3 low rectal cancer, of maximum size 4 cm, who were clinically good responders after chemoradiotherapy (residual tumour ≤2 cm) were randomly assigned before surgery to either local excision or total mesorectal excision. Randomisation was centralised and not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was performed if pathological tumour stage was ypT2-3. The primary objective of this study was to assess the 5-year oncological outcomes of local recurrence, metastatic disease, disease-free survival, overall survival, and cancer-specific mortality, which were the secondary endpoints of GRECCAR 2. We used Kaplan-Meier estimates and Cox modelling to estimate and compare recurrence and survival in modified intention-to-treat and as-treated populations. This trial was registered with ClinicalTrials.gov, number NCT00427375., Findings: Between March 1, 2007, and Sept 24, 2012, 148 patients who were good clinical responders were randomly assigned to treatment, three patients were excluded after randomisation (because they had metastatic disease, tumour >8 cm from anal verge, or withdrew consent), leaving 145 for analysis: 74 in the local excision group and 71 in the total mesorectal excision group. Median follow-up was 60 months (IQR 58-60) in the local excision group and 60 months (57-60) in the total mesorectal excision group. 23 patients died and five were lost to follow-up. In the local excision group, 26 had a completion total mesorectal excision for ypT2-3 tumour. In the modified intention-to-treat analysis, there was no difference between the local excision and total mesorectal excision groups in 5-year local recurrence (7% [95% CI 3-16] vs 7% [3-16]; adjusted hazard ratio [HR] 0·71 [95% CI 0·19-2·58]; p=0·60), metastatic disease (18% [CI 11-30] vs 19% [11-31]; 0·86 [0·36-2·06]; p=0·73), overall survival (84% [73-91] vs 82% [71-90]; 0·92 [0·38-2·22]; p=0·85), disease-free survival (70% [58-79] vs 72% [60-82]; 0·87 [0·44-1·72]; p=0·68), or cancer-specific mortality (7% [3-17] vs 10% [5-20]; 0·65 [0·17-2·49]; p=0·53)., Interpretation: The 5-year results of this multicentre randomised trial corroborate the 3-year results, providing no evidence of difference in oncological outcomes between local excision and total mesorectal excision. Local excision can be proposed in selected patients having a small T2T3 low rectal cancer with a good clinical response after chemoradiotherapy., Funding: National Cancer Institute of France., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org)., Methods: All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019., Results: The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET., Conclusion: These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients., Methods: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy., Discussion: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA., Trial Registration: NCT03519295.

Background: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting., Materials and Methods: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR)., Results: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007)., Conclusion: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF., Implications for Practice: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity., Methods: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%., Results: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%)., Conclusions: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease., Trial Registration: NCT01678664 (clinicaltrials.gov)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Following publication of improved patients' outcome using first line FOLFIRINOX for metastatic pancreatic adenocarcinoma, many physicians now prescribe it as neo-adjuvant or induction treatment for borderline and locally advanced pancreatic cancer. A pathologic complete response, rarely seen with previous preoperative regimens, is sometimes observed in these patients. The aim of this study was to assess long-term outcomes of patients presenting pathologic complete response after preoperative FOLFIRINOX usually followed by chemo-radiation therapy for non-metastatic pancreatic adenocarcinoma., Material and Methods: We retrospectively identified all resected patients with pancreatic cancer presenting pathologic complete response after FOLFIRINOX in 9 French centers from the AGEO group between November 2010 and May 2017., Results: 29 patients were enrolled, 14 had borderline, 14 locally advanced and 1 oligo-metastatic pancreatic cancer. M/F ratio was 1.2 and the mean age was 57 years. All patients were treated with FOLFIRINOX (n = 29), de-escalated to gemcitabine (n = 1) and FOLFIRI (n = 2), and 24 (83 %) received radiation therapy after chemotherapy. Objective response rate to preoperative chemotherapy was 66% (RECIST V1.1). Only 8 patients received postoperative chemotherapy. After a median follow-up of 34 months from surgery, the median overall survival was not reached and the median disease free survival was 48 months. The 1-year and 2-year survival rates were 100% for OS and 96% and 72 % for DFS from surgery, 8 of the 9 observed recurrences were distant metastases., Conclusions: The promising 1 and 2-year overall survival and disease free survival rates suggest that pathologic complete response is a major prognostic factor in resected pancreatic cancer following preoperative chemo-radiotherapy. A longer follow-up and prospective series are now necessary to confirm these encouraging results and to potentially validate pathologic complete response as a relevant surrogate marker of preoperative treatment efficacy., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Neoadjuvant chemoradiotherapy, potentially relevant to increase resection rate in pancreatic cancer, is still debated., Aims: To assess tolerance, resection rate and outcomes of patients with non-metastatic pancreatic ductal adenocarcinoma treated by concomitant chemoradiotherapy., Methods: This monocentric study included all consecutive patients treated from 2010 to 2014 for non-metastatic pancreatic adenocarcinoma. Chemotherapy was followed by chemoradiotherapy in operable patients, surgical resectability being assessed by CT-scan., Results: Seventy-nine patients were included: 41 patients had borderline and 38 locally advanced tumours. All patients were treated by chemotherapy (FOLFIRINOX), followed by chemoradiotherapy (median dose: 59 Gy, range 45-66 Gy) for 94% of patients. Thirty-seven patients (47%) could subsequently benefit from surgery with a complete R0 resection in 94% of cases, with a postoperative mortality of 5%. Median overall survival was 21.5 months (median follow-up: 48.8 months). Local control, overall and disease-free survival were significantly higher for patients who underwent resection compared to others, with 89.2% vs 59.5% (p = 0.01), 49.7 vs 17.4 months (p < 0.01) and 25.5 vs 9.2 months (p < 0.01), respectively., Conclusion: Neoadjuvant treatment consisting of FOLFIRINOX chemotherapy followed by chemoradiotherapy is an efficient strategy for patients with borderline and locally advanced pancreatic cancer, resulting in a 43% rate of secondary complete surgical resection associated with high local control, overall and disease-free survival., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Their real-life evaluation is insufficient, especially in elderly and frail patients. The aim was to describe use, safety, and effectiveness of targeted therapies in first-line mCRC treatment according to age., Patients and Methods: Two field cohorts of patients initiating bevacizumab or cetuximab for first-line mCRC were pooled. Patients characteristics, use, and safety were compared between younger and elderly patients (<75 vs. ≥75 years). Two-year overall survival (OS) and progression-free survival (PFS) were estimated in both age groups using the Kaplan-Meier method adjusted on factors associated with death or progression identified with Cox multivariate modeling., Results: Eight hundred patients (n = 411, 51.4% bevacizumab) were included: 498 (62.3%) male, median age 64 years, 118 (14.8%) Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. Elderly patients (n = 126, 15.8%) were more often treated with 5-fluorouracil alone than younger. Severe adverse events were equivalent across age groups. ECOG-PS ≥1, abnormal hemoglobin, and abnormal alkaline phosphatases were associated with a higher risk of death; OS adjusted on these factors was similar between elderly and younger patients. ECOG-PS ≥1, lung metastases, abnormal hemoglobin, and abnormal creatinine clearance were associated with a higher risk of progression or death; PFS adjusted on these factors was similar across groups., Conclusion: Despite treatment adaptations, elderly patients could benefit from targeted therapies as younger without safety warning., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We evaluated the antitumor activity and safety of avelumab, a human anti-PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy., Methods: In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5-13.9% and 1.8-16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0-not estimable) and 3.5 months (95% CI, 2.8-8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3-4.1) and 1.4 months (95% CI, 1.3-1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7-32.4%) and 7.9% (95% CI, 2.6-17.2%), and median OS was 11.1 months (95% CI, 8.9-13.7) and 6.6 months (95% CI, 5.4-9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4-20.6). Across both subgroups, 20.7% had an infusion-related reaction of any grade. Other common treatment-related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-related death., Conclusion: Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC., Trial Registration: ClinicalTrials.gov NCT01772004 ; registered 21 January 2013.

Purpose:  To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases., Materials and Methods:  This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS)., Results:  Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival., Conclusion:  This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC., Competing Interests: T. Lecomte is a consultant honorarium/advisory board member for Sanofi, and gives educational presentations to Lilly laboratory. F. Tranquart was an employee of Bracco Imaging SpA, and has been a consultant honorarium for Siemens Healthcare, General Electric Healthcare, Philips and Bracco Imaging SpA. O. Bouché is an advisory board for Roche and Merck-Sereno, and gives educational presentations to Novartis, Amgen and Lilly Laboratory. C. Borg is an advisory board for Roche and also reports receiving a research grant. No potential conflicts of interest were disclosed by the other authors., (© Georg Thieme Verlag KG Stuttgart · New York.)

The overall prognosis of patients with esophageal cancer has improved in recent decades due to surgical and medical progress, but overall survival remains poor. Better patient selection and tailored treatment are needed. Different prognostic factors linked with the patient, tumoral characteristics and treatment with curative intent have been identified and are the purpose of this review. Tumor detection at an earlier stage, the advent of new molecules and therapeutic combinations, and the centralization of management in high-volume centers should help to improve the prognosis of esophageal cancer. Improved imaging techniques and a better prediction strategy should guide future treatments., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma., Methods: We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m 2 docetaxel and 75 mg/m 2 cisplatin on day 1 and 750 mg/m 2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m 2 docetaxel and 40 mg/m 2 cisplatin on day 1 and 1200 mg/m 2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here., Findings: Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded., Interpretation: Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation., Funding: Besançon University Hospital and Ligue contre le cancer Grand-Est., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Inflammatory bowel diseases (IBD) are associated with an increased risk for colorectal cancer (CRC). However and despite significant advances in the management of IBD and CRC, the prognosis of IBD-related CRC (IBD-CRC) remains controversial. The aim of the present case-control study was to compare the prognosis of IBD-CRC to sporadic CRC., Methods: Consecutive patients operated for IBD-CRC from 2004 to 2014 were recruited and matched with sporadic CRC (ratio 3:1) from the same center. Matching was performed on gender, tumor stage, and location and period of surgery. Endpoints were postoperative morbidity (Dindo-Clavien III-V), quality of surgery, and long-term oncological outcomes., Results: Among 1498 CRC patients operated during the study period, 21 patients were identified with IBD-CRC and matched to 63 patients with sporadic CRC (S-CRC). Patients with IBD-CRC were significantly younger (p < 0.001), had multifocal lesions more frequently (p = 0.04), and undergone abdominoperineal excision and coloproctectomy more often (p = 0.001). Postoperative morbidity was not significantly different between the two groups (25 vs. 14%; p = 0.309), as well as the rate of R0 resection (86 vs. 95%; p = 0.162). Five-year disease-free and overall survival were 71 and 81% in patients with IBD-CRC and 69% (p = 0.801) and 78% (p = 0.845) in those with S-CRC, respectively., Conclusion: In a case-control study of patients operated for CRC within the last decade, the prognosis of cancer associated with IBD is similar to sporadic cancer.

Introduction: Few real-life data are available on cetuximab benefit. The EREBUS cohort was performed to assess metastases resection rate, use, safety, and survival outcomes in wild-type KRAS (Kirsten rat sarcoma viral oncogene) patients with initially unresectable metastatic colorectal cancer (mCRC) treated by cetuximab in real practice., Patients and Methods: The study cohort comprised patients initiating cetuximab between January 2009 and December 2010 in 65 French centers, with initially unresectable mCRC and wild-type KRAS. Kaplan-Meier analysis estimated 24-month probability of metastases resection and progression-free survival, and 36-month overall survival (OS). Cox proportional hazards models investigated factors associated with survival outcomes., Results: Among the 389 patients included, median age was 64 years, 67.4% were male, 77.9% had Eastern Cooperative Oncology Group performance status ≤ 1, and hepatic metastases were most frequent at baseline (n = 146 exclusively, n = 149 not exclusively, n = 94 nonliver only). Median duration of cetuximab use was 4.8 months. Metastases resection was performed in 106 patients (27.2%) (n = 60 liver exclusively, n = 33 not exclusively, n = 13 nonliver only). The 24-month probability (95% confidence interval) of metastases resection occurrence was 33.6% (28.5-39.3). Median progression-free survival was 9.2 (8.5-9.8) months for the total cohort and 13.0 (11.6-15.1) for those resected; median OS was 23.0 (20.6-26.3) months for the total cohort and was not reached after 36 months for those who were resected. The strongest factor associated with higher OS was metastases resection with complete remission (hazard ratio, 0.41; 95% confidence interval, 0.19-0.88)., Conclusion: This cohort study highlights in French real-life practice the benefit of cetuximab in first-line mCRC therapy, notably in case of metastases resection with complete remission., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Photobiomodulation therapy (PBMT) employing low-level laser therapy (LLLT) and/or light emitting diode therapy (LEDT) has emerged as an electrophysical intervention that could be associated with aerobic training to enhance beneficial effects of aerobic exercise. However, the best moment to perform irradiation with PBMT in aerobic training has not been elucidated. The aim of this study was to assess the effects of PBMT applied before and/or after each training session and to evaluate outcomes of the endurance-training program associated with PBMT. Seventy-seven healthy volunteers completed the treadmill-training protocol performed for 12 weeks, with 3 sessions per week. PBMT was performed before and/or after each training session (17 sites on each lower limb, using a cluster of 12 diodes: 4 × 905 nm super-pulsed laser diodes, 4 × 875 nm infrared LEDs, and 4 × 640 nm red LEDs, dose of 30 J per site). Volunteers were randomized in four groups according to the treatment they would receive before and after each training session: PBMT before + PBMT after, PBMT before + placebo after, placebo before + PBMT after, and placebo before + placebo after. Assessments were performed before the start of the protocol and after 4, 8, and 12 weeks of training. Primary outcome was time until exhaustion; secondary outcome measures were oxygen uptake and body fat. PBMT applied before and after aerobic exercise training sessions (PBMT before + PBMT after group) significantly increased (p < 0.05) the percentage of change of time until exhaustion and oxygen uptake compared to the group treated with placebo before and after aerobic exercise training sessions (placebo before + placebo after group) at 4th, 8th, and 12th week. PBMT applied before and after aerobic exercise training sessions (PBMT before + PBMT after group) also significantly improved (p < 0.05) the percentage of change of body fat compared to the group treated with placebo before and after aerobic exercise training sessions (placebo before + placebo after group) at 8th and 12th week. PBMT applied before and after sessions of aerobic training during 12 weeks can increase the time-to-exhaustion and oxygen uptake and also decrease the body fat in healthy volunteers when compared to placebo irradiation before and after exercise sessions. Our outcomes show that PBMT applied before and after endurance-training exercise sessions lead to improvement of endurance three times faster than exercise only.

Background: Patients with advanced neuroendocrine tumors (NETs) benefit from an increasing number of treatments. The patient's preference could help physicians to choose among these options. Our patient-reported survey aims to compare the perceived tolerance of NETs treatments., Methods: Patients treated by at least three different therapeutic options have evaluated their perceived tolerance from one (very good) to five (very poor) for each single treatment. Referent physician confirmed the type and ranking over time of each treatment., Results: Two hundred and fourty two treatments have been evaluated by 54 patients. Among patients and NETs characteristics, only a female gender was associated with poor perceived tolerance. Median perceived tolerance increased from 1 (somatostatin analogs, peptide receptor radionuclide therapy (PRRT)), 2 (surgery, radiofrequency ablation and oral chemotherapy), 3 (interferon and everolimus), to 4 (liver embolization, sunitinib and intravenous chemotherapy). In taking somatostatin analogs as reference, the odd ratios for poor perceived tolerance were 1.7 [0.6-5.1] for oral chemotherapy, 2.2 [0.9-5.3] for surgery of the primary tumor, 2.4 [0.6-9.5] for radiofrequency ablation, 2.8 [1.1-7.3] for surgery of metastasis, 3.4 [1.4-7.9] for everolimus, 3.7 [1.6-8.5] for liver embolization, 4.9 [2.2-10.7] for intravenous chemotherapy and 5.9 [2.6-13.1] for sunitinib. Only PRRT had negative odd ratio., Conclusion: Our retrospective analysis suggests that perceived tolerance differ in between therapeutic options and may help physicians to sequence the therapeutic strategy., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)