FOLFIRI3-aflibercept in previously treated patients with metastatic colorectal cancer

AIM To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer.METHODS This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3(day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m^2, irinotecan 90 mg/m^2, 5-fluorouracil infusion 2400 mg/m^2 per 46 h; day 3: irinotecan 90 mg/m^2) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate(ORR). Secondary endpoints were disease control rate(DCR), progression-free survival(PFS), overall survival(OS), and safety.RESULTS Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept(n = 3), more than one prior treatment line in irinotecanna?ve patients(n = 3), and inadequate liver function(n = 3). In the "irinotecan-na?ve" patients(n = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo(95%CI: 6.1-29.0) and 17.0 mo(95%CI: 13.0-17.3), respectively. The most common(> 5%) grade 3-4 adverse events were diarrhea(37.9%), neutropenia(14.3%), stomatitis and anemia(10.4%), and hypertension(6.7%). In the "pre-exposed irinotecan" patients(n = 35), 20(57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo(95%CI: 3.9-10.4) and 14.3 mo(95%CI: 12.8-19.5), respectively.CONCLUSION Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.

FOLFOXIRI vs FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study

BACKGROUND FOLFIRINOX regimen is the first-line reference chemotherapy(L1)in advanced pancreatic ductal adenocarcinoma(aPDAC).FOLFOXIRI,a schedule with a lower dose of irinotecan and no bolus 5-fluorouracil,has demonstrated efficacy and feasibility in colorectal cancer.AIM To investigate the potential clinical value of FOLFOXIRI in patients with aPDAC in routine clinical practice.METHODS Analyses were derived from all consecutive aPDAC patients treated in L1 between January 2011 and December 2017 in two French institutions,with either FOLFOXIRI(n=165)or FOLFIRINOX(n=124)regimens.FOLFOXIRI consisted of irinotecan(165 mg/m2),oxaliplatin(85 mg/m2),leucovorin(200 mg/m2)and 5-fluorouracil(3200 mg/m2 as a 48-h continuous infusion)every 2 wk.Ninety-six pairs of patients were selected through propensity score matching,and clinical outcomes of the two treatment regimens were compared.RESULTS Median overall survival was 11.1 mo in the FOLFOXIRI and 11.6 mo in the FOLFIRINOX cohorts,respectively.After propensity score matching,survival rates remained similar between the two regimens in terms of overall survival(hazard ratio=1.22;P=0.219)and progression-free survival(hazard ratio=1.27;P=0.120).The objective response rate was 37.1%in the FOLFOXIRI group vs 47.8%in the FOLFIRINOX group(P=0.187).Grade 3/4 toxicities occurred in 28.7%of patients in the FOLFOXIRI cohort vs 19.5%in the FOLFIRINOX cohort(P=0.079).FOLFOXIRI was associated with a higher incidence of grade 3/4 digestive adverse events.Hematopoietic growth factors were used after each chemotherapy cycle and the low hematological toxicity rates were below 5%with both regimens.CONCLUSION FOLFOXIRI is feasible in L1 in patients with aPDAC but does not confer any therapeutic benefit as compared with FOLFIRINOX.The low hematological toxicity rates strengthened the relevance of primary prophylaxis with hematopoietic growth factors.

Treatment-Induced Acute Leukaemia after Major Response to Cyclophosphamide-Based Metronomic Chemotherapy in Refractory Heavily Pre-Treated Prostate Cancer

Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtained by the administration of traditional cytotoxic drugs at lower concentration without rest periods. The low dosage induces fewer or no side effect compared to classic maximum tolerated dose administration (MTD). At present, no treatment related acute leukaemia was reported in cyclophosphamide-based metronomic chemotherapy (CMC). Case: We report the case of an 81-year-old man considered as having castration and chemo-refractory metastatic prostate cancer. CMC was started. Objective response was observed in this heavily pre-treated patient with progression free survival lasting more than 30 months. No toxicity was observed in this period and his autonomy was maintained. Finally, our patient developed a chemotherapy-induced acute myeloid leukaemia at 36th month of CMC. Conclusion: Even CMC is a well-tolerated treatment;secondary acute leukaemia is related to cumulative dose of cyclophosphamide. The benefit and the risk of long-term exposure to cyclophosphamide should be carefully balanced.

CD8^(+)CD226^(high)T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery

CD226 has been reported to participate in the rescue of CD8^(+)T cell dysfunction.In this study,we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes(TILs)derived from colorectal cancer(CRC)liver metastases treated with chemotherapy and radical surgery.TILs from 43 metastases were isolated and analyzed ex vivo usingflow cytometry.CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry.Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets.CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors.CD226 on CD8^(+)T cells was not specifically coexpressed with other immune checkpoints,such as PD1,TIGIT,and TIM3,in liver metastases.Multivariate Cox regression analysis revealed CD226 expression on CD8^(+)T cells to be an independent prognostic factor(p=0.003),along with CD3 density at invasion margins(p=0.003)and TIGIT expression on CD4^(+)T cells(p=0.019).CD155 was not associated with the prognostic value of CD226.Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors.Downregulation of CD226 on CD8^(+)TILs in the liver microenvironment was restored by IL15 treatment.Overall,CD226 expression on liver metastasis-infiltrating CD8^(+)T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.

Severe COVID-19 patients exhibit an ILC2 NKG2D^(+) population in their impaired ILC compartment

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is responsible for the current COVID-19 disease pandemic.In some patients,the symptoms are mild,and a fraction of SARS-CoV-2-infected individuals develop severe illness with a high fatality rate due to lung damage and acute respiratory distress syndrome.1 Innate lymphoid cells(ILCs)are a recently identified type of effector immune cells that rapidly sense environmental stimuli and participate in early immune responses by promptly secreting large amounts of cytokines.2 The ILC2 subpopulation was shown to mediate Type 2 responses and to recruit eosinophils during viral lung infections upon the release of alarmins(e.g.,IL-33)by damaged epithelial cells.3,4,5 ILC2s were also shown to participate in the termination of inflammatory responses and tissue repair by amphiregulin secretion.In addition,ILC2s are critical in the early phases of allergic lung inflammation,including that induced by the protease allergen papain.6 Based on the essential function of the papain-like protease PLpro in regulating SARS-CoV-27(Fig.1a)and the severe lung damage caused by this virus,we sought to investigate the potential involvement of ILC2s in immune responses to COVID-19.