Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial.

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy - a randomized phase II study -- SULTAN UCGI 30/PRODIGE 53 (NCT03164655)- study protocol.

BACKGROUND: Approximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10-15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low (< 10%). Hepatic arterial infusion (HAI) oxaliplatin may represent a salvage therapy in patients with CRLM unresectable after one or more sys-CT regimens with ORRs and CRRs up to 60 and 30%, respectively. This study is designed to evaluate the efficacy of an intensification strategy based on HAI oxaliplatin combined with sys-CT as a salvage treatment in patients with CRLM unresectable after at least 2 months of first-line induction sys-CT. OBJECTIVES AND ENDPOINTS OF THE PHASE II STUDY: Our main objective is to investigate the efficacy, in term of CRR (R0-R1), of treatment intensification in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after at least 2 months of induction sys-CT. Patients will receive either HAI oxaliplatin plus systemic FOLFIRI plus targeted therapy (i.e. anti-EGFR antibody or bevacizumab) or conventional sys-CT plus targeted therapy (i.e. anti-EGFR or antiangiogenic antibody). Secondary objectives are to compare: progression-free survival, overall survival, objective response rate, depth of response, feasibility of delivering HAI oxaliplatin including HAI catheter-related complications, and toxicity (NCI-CTCAE v4.0). METHODS: This study is a multicenter, randomized, comparative phase II trial (power, 80%; two-sided alpha-risk, 5%). Patients will be randomly assigned in a 1:1 ratio to receive HAI oxaliplatin combined with systemic FOLFIRI plus targeted therapy (experimental arm) or the best sys-CT plus targeted therapy on the basis of their first-line prior sys-CT history and current guidelines (control arm). One hundred forty patients are required to account for non-evaluable patients. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03164655). Trial registration date: 11th May 2017.

Hepatitis E Virus Infection in Patients with Chronic Inflammatory Bowel Disease Treated with Immunosuppressive Therapy.

BACKGROUND: Medical treatment of inflammatory bowel disease (IBD) has evolved significantly, and treatment with immunomodulators is recommended. These medications may alter the patient's immune response and increase the risk of opportunistic infections. Our aim was to evaluate the prevalence and the incidence of acute or chronic HEV infection in IBD patients under immunomodulatory treatment. PATIENTS AND METHODS: We conducted a retrospective, multicenter, observational study between 2017 and 2018. IBD outpatients hospitalized for the infusion of immunomodulators were included in 16 French centers. During their daily hospitalization, blood samples were drawn for HEV serology (IgM and IgG) and HEV RNA detection. RESULTS: A total of 488 patients were included, of which 327 (67%) patients had Crohn's disease and 161 (33%) ulcerative colitis. HEV IgM was detected in 3 patients, but HEV RNA was undetectable in all patients. The HEV IgG seroprevalence rate was 14.2%. IgG-positive patients were older at sampling (p = 0.01) and IBD diagnosis (p = 0.03), had higher seafood consumption (p = 0.01) and higher doses of azathioprine (p = 0.03). Ileal and upper digestive tract involvement was more frequent in IgG-positive patients (p = 0.009), and ileocolic involvement was more frequent in IgG-negative patients (p = 0.01). Under multivariate analysis, age > 50 years [OR: 2.21 (1.26, to 3.85), p = 0.004] was associated with previous HEV infection. CONCLUSION: Systematic screening for HEV infection is not needed among IBD patients on immunomodulatory medications. However, in the event of abnormal liver test findings, HEV should be part of the classic diagnostic assessment.

Daily practices in chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma: METESTOMAC French prospective cohort.

BACKGROUND: Around 50% of gastric cancers are diagnosed at an advanced stage. Several chemotherapy regimens are now internationally validated. Few data are available on the routine daily management of advanced gastric or gastroesophageal junction cancers. We aimed to describe chemotherapy practices, tolerance, and efficacy overall survival (OS) and Progression free survival (PFS) in a prospective French cohort. METHODS: Patients starting palliative chemotherapy were prospectively enrolled in 49 French centres. The primary objective was to report and describe patients' characteristics and treatment strategies. Secondary objectives were OS, PFS, objective response rate, adverse events rate, performance status deterioration during the chemotherapy. RESULTS: A total of 182 patients were included; 179 were analysed. Most patients received platinium-based chemotherapy as the first treatment and FOLFIRI as second; 62.0% of patients received a second line, and 32.4% a third line. More than two thirds of Her2-positive patients were first treated with trastuzumab. The FOLFIRI regimen was the most frequently used second-line therapy. Median OS was 13.3 months, similar whatever the chemotherapy or combinations used in the first line. One- and 2-year OS increased with the number of chemotherapy lines received, from respectively 24.7% and 5.7% (1 line), to 46.9% and 12.4% (2 lines) and 88.1% and 29.9% (3 or more lines) (p < 0.0001). CONCLUSION: Our study showed that treatment strategies in France are based on a succession of doublets, making it possible to offer a second and third line of treatment more often. This treatment strategy must be taken into account for future trials with immunotherapy combinations.

Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49.

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).

Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis.

BACKGROUND AND AIMS: There is limited data regarding the role for systemic treatment in patients with Hepatocellular Carcinoma with Child-Pugh B cirrhosis. METHODS: PRODIGE 21 was a multicentric prospective non-comparative randomized trial. Patients were randomized to receive sorafenib (Arm A), pravastatin (Arm B), sorafenib-pravastatin (Arm C) combination, or best supportive care (Arm D). Primary endpoint was time to progression (TTP), secondary endpoints included safety and overall survival (OS). RESULTS: 160 patients were randomized and 157 patients were included in the final analysis. 86% of patients were BCLC C and 55% had macrovascular invasion. The safety profiles of the drugs were as expected. Median TTP was 3.5, 2.8, 2.0 and 2.2 months in arms A, B, C and D, respectively, but analysis was limited by the number of patients deceased without radiological progression (59%). Median OS was similar between the four arms: 3.8 [95% CI: 2.4-6.5], 3.1 [95% CI: 1.9-4.3], 4.0 [95% CI: 3.2-5.5] and 3.5 months [95% CI: 2.2-5.4] in arms A, B, C and D, respectively. Median OS was 4.0 months [95% CI: 3.3-5.5] for patients treated with sorafenib, vs 2.9 months [95% CI: 2.2-3.9] for patients not treated with sorafenib. In patients with ALBI grade 1/2, median OS was 6.1 months [95% CI: 3.8-8.3] in patients treated with sorafenib vs 3.1 months [95% CI: 1.9-4.8] for patients not treated with sorafenib. CONCLUSION: In the overall Child-Pugh B population, neither sorafenib nor pravastatin seemed to provide benefit. In the ALBI grade 1/2 sub-population, our trial suggests potential benefit of sorafenib. CLINICAL TRIAL REGISTRATION: The study was referenced in clinicaltrials.gov (NCT01357486).

Baseline Splenic Volume as a Prognostic Biomarker of FOLFIRI Efficacy and a Surrogate Marker of MDSC Accumulation in Metastatic Colorectal Carcinoma.

BACKGROUND: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan. METHODS: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined. RESULTS: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank p = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank p = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank p = 0.56) or on OS (HR 0.843; log-rank p = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC (r = 0.48, p-value = 0.031). CONCLUSION: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation.