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Marine Gilabert,1,2 Jean-Luc Raoul3 1Department of Medical Oncology, Paoli-Calmettes Institute, 13232 Marseille Cedex 9, France; 2Centre de Recherche en Cancérologie de Marseille, Stress Cell Unit, Institut National de la Sante et de la Recherche Medicale 1068, Aix-Marseille University, Cedex 8, Marseille, France; 3Department of Medical Oncology, Institut de Cancérologie de l’Ouest René Gauducheau, 44805 Nantes, France Abstract: Hepatocellular carcinoma (HCC) represents ~90% of primary liver cancers and constitutes a major global health problem. Since a decade ago, the management of advanced disease that cannot be locally treated has mainly been based on multi-targeted antiangiogenic therapies. Some have demonstrated improvement in overall survival over best supportive care in first- and second-line treatment. This study focused on the efficacy of antiangiogenics in patients with advanced HCC and particularly the rising role of ramucirumab in patients with elevated alpha-fetoprotein at diagnosis. Keywords: hepatocellular carcinoma, antiangiogenic drugs, ramucirumab

Julie Bertrand,1 Fabrice Caillol,1 Patrick Borentain,2 Jean-Luc Raoul,1 Laurent Heyries,2 Erwan Bories,1 Christian Pesenti,1 Jean-Philippe Ratone,2 Jean-Paul Bernard,2 René Gerolami,2 Marc Giovannini1 1Endoscopy Unit, Paoli Calmettes Institute, Marseille, France; 2Department of Hepato-Gastroenterology, Conception Hospital, Marseille, France Abstract: Radiofrequency ablation (RFA) is a curative option for hepatocellular carcinoma (HCC), the most common primary malignancy of the liver. This bicentric retrospective study includes 46 patients admitted for their first percutaneous RFA for HCC. Sixty-three nodules were treated, with an average size of 32.5 mm. Our study confirms the efficiency of this technique for attaining necrosis of HCC nodules, with few complications. Subgroup studies according to RFA mode (mono- or multipolar), etiology of cirrhosis (alcoholic or viral), and HCC size showed better efficiency for multipolar RFA when applied to small tumors and better survival when the cirrhosis was due to viral infection. However, we noted a high rate of local recurrence in our and other recent works compared to previous studies, probably due to improved imaging techniques. The main problem is still de novo intrahepatic recurrence in diseased livers. Keywords: radiofrequency ablation, cirrhosis, HCC

Background: The drug (131)I-labeled lipiodol is used as internal radiotherapy for unresectable hepatocellular carcinoma. Although the drug was considered safe during preapproval studies, we observed several cases of interstitial pneumonia following its administration.Methods: Cases were retrospectively identified through the drug safety unit database of Rennes University Hospital.Results: From 1994 to 2009, interstitial pneumonia developed in 15 patients following (131)I-labeled lipiodol administration, with an estimated prevalence of 15.5 cases (95% CI, 7.7-23.2) per 1,000 treated patients. Mean age of the patients was 60 ± 8 years, and the male to female ratio was 6.5:1. All patients had cirrhosis, mainly related to long-term alcohol intoxication (n = 12). Most (n = 10) cases occurred after the second (131)I-labeled lipiodol injection. The median delay between last (131)I-labeled lipiodol administration and first respiratory symptoms was 30 days (interquartile range, 16.5-45 days). All patients presented with shortness of breath. Physical examination mostly revealed fever (n = 11) and bilateral crackles (n = 12). Chest CT scan showed bilateral ground-glass opacities (n = 8) with septal thickening, retraction, or both (n = 8). BAL (n = 7) was remarkable for increased neutrophils (n = 4) or CD8(+) T cell count (n = 3). Despite corticosteroids, 12 (80%) patients died, mostly of untractable respiratory failure (n = 9). Median delay between last (131)I-labeled lipiodol injection and death was 63 days (interquartile range, 34-129 days).Conclusions: Interstitial pneumonia may be a serious and not uncommon complication of (131)I-labeled lipiodol administration. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) are widely used in cancer patients despite accumulating data showing that they can impact the efficacy of major anticancer drugs. This is particularly important with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs)., Results: Most TKIs require gastric acidity for their absorption and some retrospective series demonstrated that coprescription decreases the survival benefit of some TKI use (erlotinib, gefitinib and pazopanib). Relations between microbiota, the immune system, and the efficacy of immunotherapy are now obvious, just as modifications to gut flora after PPIs use are well-known. Many retrospective articles, including articles based on individual-participant data from randomized studies, demonstrated that patients treated with CPIs have a poorer outcome (overall survival, progression-free survival and response rate) when they received PPIs concomitantly, while there was no impact of such coprescription among patients in control arms, not treated with immunotherapies. Similar data were also observed in patients treated with palbociclib., Conclusion: For these interactions, it is very important to use the precautionary principle and warn patients and physicians about this. In patients who require acid suppression because of severe symptoms, using antacids or H2 blockers could be recommended., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Despite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin., Patients and Methods: We conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4-6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival., Results: Between 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m 2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months., Conclusion: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

In controlled phase II trials, major prognostic factors need to be well balanced between arms. The main procedures used are SPBR (Stratified Permuted Block Randomization) and minimization. First, we provide a systematic review of the treatment allocation procedure used in gastrointestinal oncology controlled phase II trials published in 2019. Second, we performed simulations using data from six phase II studies to measure the impacts of imbalances and bias on the efficacy estimations. From the 40 articles analyzed, all mentioned randomization in both the title and abstract, the median number of patients included was 109, and 77.5% were multicenter. Of the 27 studies that reported at least one stratification variable, 10 included the center as a stratification variable, 10 used minimization, 9 used SBR, and 8 were unspecified. In real data studies, the imbalance increased with the number of centers. The total and marginal imbalances were higher with SBR than with minimization, and the difference increased with the number of centers. The efficiency estimates per arm were close to the original trial estimate in both procedures. Minimization is often used in cases of numerous centers and guarantees better similarity between arms for stratification variables for total and marginal imbalances in phase II trials.

Background: Longer times between diagnosis and treatments of cancer patients have been estimated as effects of the COVID-19 pandemic. However, relatively few studies attempted to estimate actual delay to treatment at the patient level., Objective: To assess changes in delays to first treatment and surgery among newly diagnosed patients with localized breast cancer (BC) during the COVID-19 pandemic., Methods: We used data from the PAPESCO-19 multicenter cohort study, which included patients from 4 French comprehensive cancer centers. We measured the delay to first treatment as the number of days between diagnosis and the first treatment regardless of whether this was neoadjuvant chemotherapy or surgery. COVID-19 pandemic exposure was estimated with a composite index that considered both the severity of the pandemic and the level of lockdown restrictions. We ran generalized linear models with a log link function and a gamma distribution to model the association between delay and the pandemic., Results: Of the 187 patients included in the analysis, the median delay to first treatment was 42 (IQR:32-54) days for patients diagnosed before and after the start of the 1st lockdown (N = 99 and 88, respectively). After adjusting for age and centers of inclusion, a higher composite pandemic index (> = 50 V.S. <50) had only a small, non-significant effect on times to treatment. Longer delays were associated with factors other than the COVID-19 pandemic., Conclusion: We found evidence of no direct impact of the pandemic on the actual delay to treatment among patients with localized BC., Competing Interests: The authors declare no conflict of interest with this research., (Copyright: © 2024 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In a multicenter prospective cohort of cancer patients (CP; n = 840) and healthcare workers (HCWs; n = 935) vaccinated against COVID-19, we noticed the following: i/after vaccination, 4.4% of HCWs and 5.8% of CP were infected; ii/no characteristic was associated with post-vaccine COVID-19 infections among HCWs; iii/CP who developed infections were younger, more frequently women (NS), more frequently had gastrointestinal, gynecological, or breast cancer and a localized cancer stage; iv/CP vaccinated while receiving chemotherapy or targeted therapy had (NS) more breakthrough infections after vaccination than those vaccinated after these treatments; the opposite was noted with radiotherapy, immunotherapy, or hormonotherapy; v/most COVID-19 infections occurred either during the Alpha wave (11/41 HCW, 20/49 CP), early after the first vaccination campaign started, or during the Omicron wave (21/41 HCW, 20/49 CP), more than 3 months after the second dose; vi/risk of infection was not associated with values of antibody titers; vii/the outcome of these COVID-19 infections after vaccination was not severe in all cases. To conclude, around 5% of our CPs or HCWs developed a COVID-19 infection despite previous vaccination. The outcome of these infections was not severe.

Background and Aims: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers., Approach and Results: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%)., Conclusions: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

New concepts and drugs have revolutionized medical treatment for cancers. These drugs, which are very expensive and usually well tolerated, have dramatically improved cancer prognosis. We must use them wisely for patients to fully benefit. Gastric acid antisecretory drugs and particularly proton pump inhibitors (PPIs) revolutionized the treatment of gastroduodenal ulcers and severe gastroesophageal reflux, but are frequently overused for symptomatic treatment of epigastric pain or heartburn. Long-term acid suppression may alter the efficacy of many anticancer drugs, such as tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors (ICIs), by either decreasing gastric acid secretion and thus drug absorption, or by modifying the gut microbiome that modulates the response to ICIs. Oncologists thus need to pay particular attention to the concomitant use of PPIs and anticancer drugs. These interactions translate into major clinical impacts, with demonstrated loss of efficacy for some TKIs (erlotinib, gefitinib, pazopanib), and conflicting results with many other oral drugs, including capecitabine and CDK 4/6 inhibitors. Furthermore, the profound changes in the gut microbiome due to using PPIs have shown that the benefit of using ICIs may be suppressed in patients treated with PPIs. As the use of PPIs is not essential, we must apply the precautionary principle. The first sentence of a recent Comment in Nature was "Every day, millions of people are taking medications that will not help them". We fear that every day millions of cancer patients are taking medications that harm them. While this may well be only association and not causation, there is enough to make us pause until we reach a clear answer. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The standard of care of first-line systemic therapy for advanced hepatocellular carcinoma (HCC) is currently changing with the results of the IMbrave150 trial which are demonstrating superiority of the atezolizumab-bevacizumab combination over sorafenib, modifying this line of treatment for the first time in over 10 years. Recently, other immunotherapy-based combinations (durvalumab-tremelimumab, lenvatinib-pembrolizumab, cabozantinib-atezolizumab, and camrelizumab-rivoceranib) reported results in phase III studies, and might challenge this new standard of care. This revolution will lead to a considerable change in practice, and highlight challenges for future drug development. In this review, we will, firstly, describe results of the different combinations, and discuss the difficulties in selecting the first-line treatment. We will then present the different recommendations about second-line treatment following the first-line immunotherapy-based combination, discussing the rationale for the differences in existing recommendations. We will finally discuss the challenges for future drug development in advanced HCC.

In this prospective, real-life cohort study, we followed 523 cancer patients (CP) and 579 healthcare workers (HCW) from two cancer centers to evaluate the biological and clinical results of the COVID-19 vaccination campaign. Seventy percent of the CP and 90% of the HCW received an mRNA vaccine or the AZD1222 vaccine. Seropositivity was high after the first vaccine among HCW and poor among CP. The second dose resulted in almost 100% seropositivity in both cohorts. Antibody response was higher after the second injection than the first in both populations. Despite at least two doses, 8 CP (1.5%) and 14 HCW (2.4%) were infected, corresponding either to a weak level of antibody or a new strain of virus (particularly the Omicron variant of concern). Sixteen CP and three HCW were hospitalized but none of them died from COVID-19. To conclude, this study showed that two doses of COVID-19 vaccines were crucially necessary to attain sufficient seropositivity. However, the post-vaccination antibody level declines in individuals from the two cohorts and could not totally prevent new SARS-CoV-2 infections.

The absorption of pazopanib depends on gastric pH. PPIs are frequently prescribed for cancer patients to modify gastric acidity, decreasing pazopanib absorption. The aim of our study was, retrospectively, to investigate the impact of PPIs on the clinical efficacy and safety of pazopanib in a cohort of patients treated in our health center. Of the 147 patients who were included retrospectively, 79 (54%) did not take PPIs concomitantly with pazopanib (cohort 1), while 68 (46%) patients did take PPIs concomitantly with pazopanib (cohort 2). The efficacy parameters were lower in patients taking pazopanib and PPIs: the i/tumor response was statistically different between the two cohorts (p = 0.008), in particular, with 19% vs. 3% of the objective response and 24% vs. 43% of progression in cohorts 1 and 2, respectively; ii/median overall survival was 17.6 (95% CI: 12.5−32.8) months in cohort 1 and 8.6 months (95% CI: 5.9−18.6) in cohort 2 (HR = 1.7 [95% CI: 1.2−2.5]; p < 0.006); on multivariable analysis, overall survival was associated with performance status, PPI intake, tumor location, hemoglobin, and PMN/lymphocyte ratio. In contrast, the dose reduction for toxicity and severe adverse events were (non-significantly) less frequent in cohort 1. To conclude, our study shows that combining PPIs with pazopanib has an adverse effect on overall survival. The clinical modifications that were observed are in line with a decrease in pazopanib absorption due to PPIs. This co-medication should be avoided.

Background: Cancer patients (CPs) are considered more vulnerable and as a high mortality group regarding COVID-19. In this analysis, we aimed to describe asymptomatic COVID (+) CPs and associated factors., Methods: We conducted a prospective study in CPs and health care workers (HCWs) in 4 French cancer centers (PAPESCO [ PAtients et PErsonnels de Santé des Centres de Lutte Contre le Cancer pendant l'épidémie de COvid-19 ] study). This analysis used data recorded between June 17, 2020 and November 30, 2020 in CPs (first 2 waves, no variants). At inclusion and quarterly, CPs reported the presence of predefined COVID-19 symptoms and had a blood rapid diagnostic test; a reverse transcription polymerase chain reaction (RT-PCR) was done in case of suspected infection., Results: A total 878 CPs were included; COVID-19 prevalence was similar in both CPs (8%) and HCWs (9.5%); of the 70 CPs (8%) who were COVID (+), 29 (41.4%) were and remained asymptomatic; 241/808 of the COVID (-) (29.8%) were symptomatic. 18 COVID (+) were hospitalized (2% of CPs), 1 in intensive care unit (ICU) and 1 died (0.1% of CPs and 2.4% of symptomatic COVID [+] CPs). Only the inclusion center was associated with clinical presentation (in Nancy, Angers, Nantes, and Clermont-Ferrand: 65.4%, 35%, 28.6%, and 10% CPs were asymptomatic, respectively)., Conclusions: Seroprevalence of COVID-19 in CPs was similar to that observed in HCWs; mortality related to COVID-19 among CPs was 0.1%. More than 40% of COVID (+) CPs were asymptomatic and one third of COVID (-) CPs had symptoms. Only geographic origin was associated with the presence or absence of symptoms. Social distancing and protective measures must be applied in CPs at home and when hospitalized., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Nowadays, resection of two (liver and peritoneum) concomitant colorectal cancer metastatic sites is no longer contraindicated. However, the oncologic outcomes of resecting peritoneal metastases (PM) occurring more than six months after resection of liver metastases (LM) are unknown., Aim: The aim of this study was to compare patients with complete cytoreductive surgery (CRS) with or without a history of previous liver resection (LR)., Methods: Analysis from a prospective database of 74 patients with metachronous PM treated with CRS between 2010 and 2020., Results: All patients had PM metachronous to primary, 64 patients underwent CRS alone (CRSa) and 10 CRS more than six months after LR (LR-CRS). There was no statistical difference between the groups for clinical or therapeutic characteristics. There were more signet ring cell/mucinous adenocarcinomas in the CRSa group than in the LR-CRS group (19% vs. 0%, p = 0.049). The median peritoneal cancer index (PCI) was 4 and 6 (p = 0.749) in the LR-CRS and CRSa groups, respectively. Median overall survival (OS) and disease-free survival (DFS) were not statistically different between the two groups with 43.6 and 13 months for the CRSa group and 31.1 months and 9.4 months for LR-CRS. Advanced age was an independent negative prognostic factor for OS and high PCI was limit significant. No prognostic factor for DFS was found., Conclusions: LR before CRS has no major prognostic impact. Resection of iterative liver and peritoneum metastases can achieve long-term survival., Competing Interests: Declaration of competing interest No funding or other financial support was received for this work. The authors declare no potential conflict of interest with reference to this article., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method for intraabdominal cavity chemotherapy. It combines the benefits of a minimally invasive approach (low morbidity and easy to repeat) with the pharmacokinetic advantages of intraperitoneal administration and tolerance seems excellent. We would like to report one case of a serious adverse event, acute respiratory distress syndrome, which is likely related to oxaliplatin administration; all signs disappeared within a few days., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2021 Emilie Thibaudeau et al., published by De Gruyter, Berlin/Boston.)

Background: Cancer patients may fail to distinguish COVID-19 symptoms such as anosmia, dysgeusia/ageusia, anorexia, headache, and fatigue, which are frequent after cancer treatments. We aimed to identify symptoms associated with COVID-19 and to assess the strength of their association in cancer and cancer-free populations. Methods: The multicenter cohort study PAPESCO-19 included 878 cancer patients and 940 healthcare workers (HCWs). At baseline and quarterly thereafter, they reported the presence or absence of 13 COVID-19 symptoms observed over 3 months and the results of routine screening RT-PCR, and they were systematically tested for SARS-CoV-2-specific antibodies. We identified the symptom combinations significantly associated with COVID-19. Results: Eight percent of cancer patients were COVID-19 positive, and 32% were symptomatic. Among the HCWs, these proportions were 9.5 and 52%, respectively. Anosmia, anorexia, fever, headache, and rhinorrhea together accurately discriminated (c-statistic = 0.7027) COVID-19 cases from cancer patients. Anosmia, dysgeusia/ageusia, muscle pain, intense fatigue, headache, and chest pain better discriminated (c-statistic = 0.8830) COVID-19 cases among the HCWs. Anosmia had the strongest association in both the cancer patients (OR = 7.48, 95% CI: 2.96-18.89) and HCWs (OR = 5.71, 95% CI: 2.21-14.75). Conclusions: COVID-19 symptoms and their diagnostic performance differ in the cancer patients and HCWs. Anosmia is associated with COVID-19 in cancer patients, while dysgeusia/ageusia is not. Cancer patients deserve tailored preventive measures due to their particular COVID-19 symptom pattern.

Background: Careful selection of hepatocellular carcinoma (HCC) patients prior to chemoembolization treatment is a daily reality, and is even more necessary with new available therapeutic options in HCC., Aim: To propose two new models to better stratify patients and maximize clinical benefit: "6 and 12" and "pre/post-TACE-predict" (TACE, transarterial chemoembolization)., Methods: We evaluated and compared their performance in predicting overall survival with other systems {Barcelona Clinic Liver Cancer (BCLC), Albumin-Bilirubin (ALBI) and NIACE [Number of tumor(s), Infiltrative HCC, alpha-fetoprotein, Child-Pugh (CP), and performance status]} in two HCC French cohorts of different stages enrolled between 2010 and 2018., Results: The cohorts included 324 patients classified as BCLC stages A/B (cohort 1) and 137 patients classified as BCLC stages B/C (cohort 2). The majority of the patients had cirrhosis with preserved liver function. "Pre-TACE-predict" and "6 and 12" models identified three distinct categories of patients exhibiting different prognosis in cohort 1. However, their prognostic value was no better than the BCLC system or NIACE score. Liver function based on CP and ALBI grades significantly impacted patient survival. Conversely, the "post-TACE-predict" model had a higher predictive value than other models. The stratification ability as well as predictive performance of these new models in an intermediate/advanced stage population was less efficient (cohort 2)., Conclusion: The newly proposed "Pre-TACE-predict" and "6 and 12" models offer an interesting stratification into three categories in a recommended TACE population, as they identify poor candidates, those with partial control and durable response. The models' contribution was reduced in a population with advanced stage HCCs., Competing Interests: Conflict-of-interest statement: The authors have no potential conflict of interest relative to this article. Adhoute X: Board member (Bayer, Ipsen, Eisai); Grant from Ipsen, Eisai. Anty R: Board member (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen). Chevallier P: Board member (Bayer). Tran A: Board member (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen). Bronowicki JP: Board member (Merck-Schering Plough, Janssen, Roche, BMS, Boehringer-Ingelheim, Gilead, Novartis, GSK, Bayer). Raoul JL: Board member (Bayer, BMS, Daichi). Castellani P: Board member (Gilead). Bourlière M: Board member (Merck-Schering Plough, Gilead, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, GSK). Pénaranda G, Perrier H, Monnet O, Bayle O and Pol B have no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background/aim: FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX., Patients and Methods: We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board., Results: Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and 18 F-FDG PET positivity., Conclusion: FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background : Stereotactic body radiotherapy (SBRT) is a recognized treatment for colorectal cancer (CRC) metastases. We postulated that local responses could be improved by SBRT with a concomitant radiosensitizing agent (irinotecan). Methods : RADIOSTEREO-CAMPTO was a prospective multi-center phase 2 trial investigating SBRT (40-48 Gy in 4 fractions) for liver and/or lung inoperable CRC oligometastases (≤3), combined with two weekly intravenous infusions of 40 mg/m 2 Irinotecan. Primary outcome was the objective local response rate as per RECIST. Secondary outcomes were early and late toxicities, EORTC QLQ-C30 quality of life, local control and overall survival. Results : Forty-four patients with 51 lesions (liver = 39, lungs = 12) were included. Median age was 69 years (46-84); 37 patients (84%) had received at least two prior chemotherapy treatments. Median follow-up was 48.9 months. One patient with two lung lesions was lost during follow-up. Assuming maximum bias hypothesis, the objective local response rate in ITT was 86.3% (44/51-95% CI: [76.8-95.7]) or 82.4% (42/51-95% CI: [71.9-92.8]). The observed local response rate was 85.7% (42/49-95% CI: [75.9-95.5]). The 1 and 2-year local (distant) progression-free survivals were 84.2% (38.4%) and 67.4% (21.3%), respectively. The 1 and 2-year overall survivals were 97.5% and 75.5%. There were no severe acute or late reactions. The EORTC questionnaire scores did not significantly worsen during or after treatment. Conclusions : SBRT with irinotecan was well tolerated with promising results despite heavily pretreated patients.

Objective: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers., Methods: PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m 2 with planned increases of 50 mg/m 2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252)., Results: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m 2 and two at 140 mg/m 2 . The MTD was therefore set at 90 mg/m 2 . Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m 2 , the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC) 0-48h of 1035 μg/l and 9028 μg h/L, respectively., Conclusions: The MTD of oxaliplatin during PIPAC is 90 mg/m 2 . PK data demonstrate a high tumour concentration and a significant systemic absorption., Competing Interests: Conflict of interest statement O.G. received honoraria from Gamida. The others authors have no interest conflict to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The "six-and-twelve" (6&12) score is a new hepatocellular carcinoma (HCC) prognostic index designed for recommended transarterial chemoembolization (TACE) candidates. Quick and easy to use by the sum of tumor size (cm) and number, this model identifies three groups with different survival time (the sum is ≤ 6; or > 6 but ≤ 12; or > 12); a survival benefit with TACE can be expected for HCC patients with a score not exceeding twelve. Recently, Wang ZW et al showed that the "6&12" model was the best system correlated with radiological response after the first TACE. Thus, we wanted to assess its survival prediction ability as well as its prognostic value and compared it to other systems (Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer (HKLC) staging, Albumin-Bilirubin grade, tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, Child-Pugh class, and Performance Status score, Cancer of the Liver Italian Program, Model to Estimate Survival for HCC scores, up-to-seven criteria) different from Wang ZW et al study in a multicenter French cohort of HCC including only recommended TACE candidates retrospectively enrolled. As previously demonstrated, we show that the "6&12" score can classify survival within this French cohort, with a prognostic value comparable to that of other systems, except HKLC staging. More importantly, the "6&12" score simplicity and ability in patients' stratification outperform other systems for a routine clinical practice., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

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: Peritoneal recurrences from colo-rectal cancer can be isolated (PR) or associated with local recurrences (LR). The purpose of this study was to analyze patterns and outcomes of LR and PR., Methods: Analyze from a prospective database of 108 patients treated with CCS plus HIPEC at two cancer centers between 2008 and 2015., Results: The population was divided into an LPR group (presence of LR with or without PR, n = 56) and a PR group (isolated PR, n = 52). The patients characteristics (age, sex, Charlson score, PCI) or perioperative treatments were comparable between the groups. The median number of resected organs for tumor involvement (respectively, 2 vs 1; p < 0.001), the percentage of patients with metastatic lymph nodes (LN+) from the resected specimen (respectively, 25% vs 7%; p = 0.016) and the mortality rate (respectively, 9% vs 0%; p = 0.023) were significantly higher in the LPR group. After a median follow-up of 32 (1-108) months, median overall survival was comparable between the two groups (respectively, 46 vs 42 months; p = 0.262)., Conclusions: LR is associated with a higher incidence of organ invasion, LN involvement (25%) and postoperative mortality. Optimal surgical resection of LR with systematic lymphadenectomy of invaded organs seems mandatory., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Conventional transarterial chemoembolization (cTACE) with lipiodol is widely performed in patients with hepatocellular carcinoma (HCC) unsuitable for curative treatment. Additional tumor parameters such as HCC macroscopic appearance based on imaging might be helpful for transarterial chemoembolization prognostication and management., Patients and Methods: A total of 405 patients with HCC who underwent cTACE between 2008 and 2016 from a real-life multicenter French cohort were retrospectively reviewed. Tumors were classified into two macroscopic types according to HCC gross appearance on imaging: nodular versus non-nodular. The study population was stratified into two groups: derivation and validation cohorts. Independent prognostic factors of survival based on multivariate cox regression models were determined and then assessed in the validation set. Thereafter, time to progression (TTP) and radiological response rate were investigated for each prognostic factors of survival., Results: Median overall survival (OS) was 35 months for Barcelona Clinic Liver Cancer (BCLC) stage A, 22 months for BCLC stage B and 12 months for BCLC stage C patients (P < 0.0001). The corresponding TTP for these patients was 12 (7-17) months, 5 (3-6) months and 1.2 (1.2-3) months (P < 0.0001). Multivariate analysis revealed that tumors size and number, non-nodular type, alpha-fetoprotein, aspartate aminotransferase serum levels and impairment of performance status-1 were independent predictors of survival among the study groups. Non-nodular type was the most powerful factor that influences OS, TTP and radiological response rate for the recommended transarterial chemoembolization candidates. TTP was consistent with OS within each stage., Conclusion: HCC macroscopic appearance on imaging is a determinant predictor of outcome after cTACE in a real-life multicenter cohort.

Background: Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). The management of its side effects is improving. This study aimed to assess, in real life, if this translates into a better prognosis., Methods: This was a retrospective study of advanced HCC patients treated with sorafenib between 2007 and 2017., Results: 188 advanced HCC patients received > 4 weeks of sorafenib. Median treatment duration was 5.4 months and median overall survival (mOS) 10 months (95% confidence interval 15-27). Sorafenib was initiated in 65 patients in 2007-2012 and 123 in 2013-2017. Both groups were comparable except for Barcelona Clinic liver cancer class. Tumor progression, disease control (DC) rate, and incidence of toxicity were similar in the 2 periods, but the duration of treatment (4.3 vs. 5.9 months; p < 0.01) and mOS (8 vs. 12 months; p < 0.002) differed. Among progressive disease patients, mOS was similar (7 months) but for those who had DC at 8 weeks, mOS was longer in the recent period (13 vs. 27 months; p < 0.0001). In the univariate analysis of OS, the period of treatment had a prognostic value., Conclusion: When comparing 2 periods of treatment in advanced HCC patients under sorafenib, duration of treatment and mOS were higher in the recent period. While mOS did not differ for patients who progressed, it was 2-fold higher in the recent period for those who had tumor control. Improvements in the use of sorafenib seem to be associated with better outcomes limited to patients with DC., Competing Interests: JLR is a Board member of Bayer, BMS, BTG, Terumo, and Astra-Zeneca. XA is a Board member of Bayer. GP grant from Bayer; MB is a Board member of Merck-Schering Plough, Janssen, Roche, Gilead, Novartis, and Bayer., (Copyright © 2019 by S. Karger AG, Basel.)

Background: There are few data on lymphatic spread concomitant to local recurrence (LR) of colorectal cancer (CRC). The objectives of this study were to determine variables associated with lymphatic spread, to analyze the distribution of LN+, and understand the underlying mechanisms., Methods: A total of 76 patients underwent resection of LR of CRC between January 2007 and December 2018 at Institut cancérologique de l'Ouest and were retrospectively reviewed., Results: Twenty-five (32.9%) patients had lymph node (LN) involvement with LR. Lymphatics from the mesocolon-rectum and aorto-iliac compartments were involved in 21%, 20.3% and 18.1%, 20.3% for pelvic and retroperitoneal LRs, respectively. In multivariate analysis, the only predictive factor for LN invasion (LN+) was a primary positive LN status (odds ratio, 5.3; P = .007). Despite a trend toward a worse median overall survival in the LN+ group, the difference was not significant in comparison with the LN- group (46 vs. 57 months; P = 0.31) or with the LN- plus LN not assessed groups (46 months vs not reached; P = .07)., Conclusions: LN invasion with LR from CRC is a frequent occurrence without significant impact on survival. The only predictive factor is a primary positive nodal status., (© 2019 Wiley Periodicals, Inc.)

Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma., Patients and Methods: This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracil 400 mg/m 2 bolus then 2400 mg/m 2 over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance., Results: The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%)., Conclusions: We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinoma patients., Trial Registration: European Clinical Trials Database, number 2009-012797-12., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Circulating Tumor Cells (CTCs) represent an easy, repeatable and representative access to information regarding solid tumors. However, their detection remains difficult because of their paucity, their short half-life, and the lack of reliable surface biomarkers. Flow cytometry (FC) is a fast, sensitive and affordable technique, ideal for rare cells detection. Adapted to CTCs detection (i.e. extremely rare cells), most FC-based techniques require a time-consuming pre-enrichment step, followed by a 2-hours staining procedure, impeding on the efficiency of CTCs detection. We overcame these caveats and reduced the procedure to less than one hour, with minimal manipulation. First, cells were simultaneously fixed, permeabilized, then stained. Second, using low-speed FC acquisition conditions and two discriminators (cell size and pan-cytokeratin expression), we suppressed the pre-enrichment step. Applied to blood from donors with or without known malignant diseases, this protocol ensures a high recovery of the cells of interest independently of their epithelial-mesenchymal plasticity and can predict which samples are derived from cancer donors. This proof-of-concept study lays the bases of a sensitive tool to detect CTCs from a small amount of blood upstream of in-depth analyses.

Most hepatocellular carcinoma patients could not benefit from or experience disease recurrence after curative treatments. In 2007 sorafenib demonstrated efficacy in first line treatment of advanced hepatocellular carcinoma. After a decade of negative trials, in early 2019 we now have another tyrosine kinase inhibitor available in first line, lenvatinib, three other targeted therapies in second line post-sorafenib (regorafenib, cabozantinib and ramucirumab) and promising data from two immunotherapies (nivolumab and pembrolizumab). Unfortunately, no biomarkers have been identified to help guide our choice. In this short review we summarize the results of these different therapies and propose a therapeutic algorithm based on subgroup analysis. It is most likely that we will not have head-to-head comparisons in second line trials., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, representing the sixth leading cause of cancer and the third leading cause of cancer-related mortality. Patient stratification and treatment allocation are based on tumor stage, liver function, and performance status. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate stage HCC, including those with large or multinodular HCC, well-preserved liver function, and no cancer-related symptoms or evidence of vascular invasion or extrahepatic spread. Two TACE techniques have been used since 2004, conventional TACE (cTACE) and TACE with drug-eluting beads (DEB-TACE). cTACE was evidenced first to treat intermediate stage HCC patients. It combines the transcatheter delivery of chemotherapy using Lipiodol-based emulsion plus an embolizing agent to achieve strong cytotoxic and ischemic effects. Drug-eluting beads (DEBs) were developed in order to slowly release chemotherapeutic agents, and to increase ischemia intensity and duration. Recent advances allow TACE treatment of both early stage patients (i.e. those with a solitary nodule or up to 3 nodules under 3 cm) and some advanced stage patients. Here we review recent clinical evidence related to TACE treatment of patients with early, intermediate, and advanced stage HCC. Based on the 2014 TACE algorithm of Raoul et al., this international expert panel proposes an updated TACE algorithm and provides insights into TACE use for patients at any HCC stage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Objectives: Subepithelial lesions (SELs) of the upper part of the digestive tract are rare, and it can be difficult to characterize them. Recently, contrast-enhanced endosonography (EUS) and elastometry have been reported as useful adjuncts to EUS and EUS-guided fine needle aspiration (EUS-FNA) in cases of pancreatic mass and lymph node involvement. The aim of this retrospective analysis was to evaluate whether contrast-enhanced EUS can discriminate benign submucosal lesions from malignant ones. We describe our retrospective experience using the contrast agent SonoVue ® (Bracco Imaging, Milan, Italy) in an attempt to increase the diagnostic yield., Patients and Methods: Between May 2011 and September 2014, 14 patients (5 men, 9 women; median age 64 years, range 31-80 years) with SELs of the stomach or esophagus underwent EUS with SonoVue ® (low mechanical index). There were 3 esophageal lesions and 11 gastric lesions. Mean size of the lesions was 30 mm (range 11-50 mm). They were discovered after anemia (n = 5), dysphagia (n = 1), and pain (n = 4) and during follow-up for resected gastrointestinal stromal tumors (GISTs) (n = 1) and a standard upper gastrointestinal endoscopy (n = 3). On endoscopic sonograms, 10 of these lesions were hypoechoic and located in the fourth layer (muscularis), and 4 were in the second or third layer (mucosa and submucosa). Contrast enhancement was assessed in the early phase (after several seconds) and late phase (>30 seconds); a final diagnosis was made based on the findings of EUS-FNA using a 19-gauge ProCore (Cook Medical, Bloomington, IN) (n = 9) or 22-gauge FNA system (Cook Medical) (n = 1), the resected specimen (n = 3), or deep biopsy (n = 1). Different immunostaining was used in the pathologic studies (RNA was analyzed later using the C-kit, CD-117, CD-34, desmin, DOG-1, α-smooth actin, caldesmon, PS-100, and Ki-67 antibodies)., Results: Final diagnoses were leiomyoma (n = 4), GIST (n = 5), schwannoma (n = 1), inflammatory tumor of Helvig (n = 1), pancreas rest (n = 2), and fibrosis (n = 1). No complications occurred. All 5 GISTs showed enhancement in the early and late phases, whereas the 8 remaining lesions did not show any enhancement. Only 1 leiomyoma showed heterogeneous enhancement., Limitations: The monocentric and retrospective study design and small number of patients., Conclusions: In cases of SELs of the stomach or esophagus, SonoVue ® could be a complementary tool to endosonography to differentiate GISTs (early and clear enhancement) from other SELs (few or no enhancement), such as leiomyomas or pancreatic rest. These results are similar to those of the few, small studies published on this topic, but more studies with a larger number of patients are needed to confirm these findings., Competing Interests: None