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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.)

Background: Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers., Methods: In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m(2)) and oxaliplatin (100 mg/m(2)) with or without cetuximab (500 mg/m(2)), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149., Findings: Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52-74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43-65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1-7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7-6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1-13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6-16·0) in the chemotherapy alone group. The most common grade 3-4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group., Interpretation: The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option., Funding: Institut National du Cancer, Merck Serono., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer., Methods: In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256., Findings: 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group., Interpretation: Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer., Funding: Sanofi-Aventis France., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.