Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

Background Mutation status of RAS and BRAF , as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study. Methods CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2–4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 µg/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status. Results For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS). Conclusions High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF -mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.

ObjectivesThe aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status.ResultsHigh levels of pretreatment serum IL-6 or CRP were associated with impaired outcome, in terms of reduced PFS and OS. Patients with low versus high serum IL-6 levels had median OS of 26.0 versus 16.6 months, respectively (P < 0.001). Stratified according to increasing CRP levels, median OS varied from 24.3 months to 12.3 months, (P < 0.001). IL-6 and CRP levels affected overall prognosis also in adjusted analyses. The effect of IL-6 was particularly pronounced in patients with BRAF mutation (interaction P = 0.004).Materials and MethodsIL-6 and CRP were determined in pre-treatment serum samples from 393 patients included in the NORDIC-VII trial, in which patients with mCRC received first line treatment. The effect of serum IL-6 and CRP on progression-free survival (PFS) and overall survival (OS) was estimated.ConclusionsHigh baseline serum consentrations of IL-6 or CRP were associated with impaired prognosis in mCRC. IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status.

Primary monolayer cultures of rat hepatocytes were used for studies of long-term and acute effects of hormones on the cyclic AMP system. When hepatocyte lysates were assayed at various times after plating of the cells three major changes in the metabolism of cyclic AMP and its regulation were observed : Glucagon-sensitive adenylate cyclase activity gradually declined in culture. In contrast, catecholamine-sensitive activity, being very low in normal adult male rat liver and freshly isolated hepatocytes, showed a strong and rapid increase after seeding of the cells. Concomitantly, there was an early elevation (peak z 6 h) and a subsequent decrease in activity of both high-& and low-K, cyclic AMP phosphodiesterase. These enzymic changes probably explained the finding that in intact cultured cells the cyclic AMP response to glucagon was diminished for 2-24 h after seeding, followed by an increase in the responsiveness to glucagon as well as to adrenergic agents up to 48 h of culture. Supplementation of the culture media with dexamethasone and/or insulin influenced the formation and breakdown of cyclic AMP in the hepatocytes. Insulin added at the time of plating moderately increased the adenylate cyclase activity assayed at 48 h, while dexamethasone had no significant effect. In the presence of dexamethasone, insulin exerted a stronger, and dosedependent (1 pM-1 pM), elevation of the adenylate cyclase activity in the lysates, particularly of the glucagon responsiveness. Thus, insulin plus dexamethasone counteracted the loss of glucagon-sensitive adenylate cyclase activity occurring in vitro. Kinetic plots of the cyclic AMP phosphodiesterase activity showed three affinity regions for the substrate. Of these, the two with high and intermediate substrate affinity (K, x 1 and x 10 pM) were decreased in the dexamethasone-treated cells. Insulin partly prevented this effect of dexamethasone. Accumulation of cyclic AMP in intact cells in response to glucagon or P-adrenergic agents was strongly increased in cultures pretreated with dexamethasone. The results suggest that insulin and glucocorticoids modulate the effects of glucagon and epinephrine on hepatocytes by exerting long-term influences on the cyclic AMP system. Hepatocytes maintained in vitro as primary cultures [I -101 offer an attractive experimental tool, not only due to the potential usefulness of these cells in investigations of the biology and pharmacology of liver [ll-131, but also because relatively few other model systems exist for long term studies of differentiated epithelial cells in vitro under controlled conditions.We have investigated the cyclic AMP system and its regulation in primary monolayer cultures of adult rat hepatocytes. The studies first intended to explore if the hepatocytes in culture maintain normal formation and degradation of cyclic AMP. Hepatocytes in monolayer possess the enzymes involved in cyclic AMP metabolism [5,, but relatively few details are known. Our results indicate that the cells in culture retain hormone sensitivity, but al...

365 Background: The role of anti-EGFR therapy in first-line treatment of metastatic colorectal cancer (mCRC) is not established. In the present study pts were randomized to FLOX or FLOX + cetuximab until progression or FLOX intermittently + cetuximab continuously. Methods: Treatment arm A: Nordic FLOX (q2w): oxaliplatin 85 mg/m2day 1, 5-FU bolus 500 mg/m2 and FA 60 mg/m2 day 1-2; B: FLOX + cetuximab, initial dose 400 mg/m2, then 250 mg/m2/week; C: FLOX for 16 weeks + cetuximab continuously, with FLOX added at progression. Primary endpoint was progression-free survival (PFS). Results: Between May 05-Oct 07, 571 pts were randomized, 566 pts evaluable in intention to treat (ITT) analyses. Median age was 61 (24-74). ECOG status: 0=67%, 1=29%, 2=4%. KRAS and BRAF mutation (mut) analyses were obtained in 498 (87%) and 457 pts (81%), respectively. 40% of tumors had KRAS mut, 12% had BRAF mut. Cetuximab combined with Nordic FLOX did not significantly improve RR, PFS or OS compared to FLOX. KRAS mutation was not predictive for cetuximab effect. OS was similar for patients treated with FLOX intermittently and cetuximab continuously as for patients treated until progression. BRAF mutation was a strong negative prognostic factor (median OS 7.6 vs. 20.4 mo). Conclusions: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC, irrespective of KRAS-mut. [Table: see text] [Table: see text]