Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer.

BACKGROUND: The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients. METHODS: In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee. RESULTS: From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ≥3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months. CONCLUSIONS: The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2. TRIAL REGISTRATION: http://www.clinicaltrials.gov: NCT00422773.

Defined criteria for resectability improves rates of secondary resection after systemic therapy for liver limited metastatic colorectal cancer.

AIMS: Long-term survival has been demonstrated for patients with irresectable colorectal liver metastases who are brought to resection by chemotherapy. However, it remains unclear whether improved long-term outcome seen with modern therapies translates to increased rates of secondary resection and whether response rates correlate with rates of secondary liver resection. METHODS: A systematic review of literature published between January 1998 and September 2013 was performed. Phase II/III trials were included if they reported the rate of objective response and the rate of secondary resection of initially irresectable metastases. For the phase III trials, the ratio between response and resection rates within the trials was investigated as well as the correlation for both parameters in all trials. RESULTS: Twenty-five studies were identified. Response rate demonstrated a strong correlation with rates of secondary resection (R(2)=0.44, p=0.008). Ratios of response/resection between both arms of 10 randomised control trials (RCTs) were calculated to control for selection bias, and showed that in a randomised setting response rates correlate with increased rates of secondary resection in an intra-trial comparison (R(2)=0.87, p=0.002). Linear regression analysis demonstrated a significant difference between studies where criteria for resectability were defined (median 39.5%), and those where it was not (median 11%) (p=0.006). CONCLUSION: There is a clear correlation between radiological response and rates of secondary resection, with studies that define resectability achieving much higher rates. All trials investigating first line treatment in patients with metastatic colorectal cancer should have criteria for resection, with conversion to secondary resection as a defined study end-point.

Preoperative high-dose steroid administration attenuates the surgical stress response following liver resection: results of a prospective randomized study.

BACKGROUND/PURPOSE: Major abdominal surgery such as liver resection is associated with an excessive hyperinflammatory response and transient immunosuppression. We investigated the immunomodulating effect of preoperative pulse administration of high-dose methylprednisolone in patients undergoing hepatic resection without pedicle clamping. METHODS: Twenty patients who underwent hepatic resection were randomized into two groups: a steroid group (n = 10), in which patients were given 30 mg/kg per body weight (BW) methylprednisolone intravenously, and a control group (n = 10), in which patients received a placebo (sodium chloride) infusion. The main outcome parameter to assess systemic stress was the serum plasma level of interleukin-6 (IL-6). To evaluate cell-mediated immune function, human leukocyte antigen-DR (HLA-DR) expression on peripheral blood monocytes and lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) release by peripheral monocytes was measured. Other investigated serum parameters included C-reactive protein (CRP), total bilirubin, alanine aminotransferase (ALT), prothrombin time (PT)-INR, and cytokines such as IL-8 and IL-10 and TNF-alpha. Postoperative convalescence, complication rate, and length of hospital stay were compared between the groups. RESULTS: Postoperative plasma concentrations of IL-6 (days 1 and 2), IL-8 (days 2 and 3), and CRP (days 1-4) were significantly lower in the steroid than in the control group. The total bilirubin concentration was significantly lower on day 6 in the steroid than in the control group. Four hours after surgery, LPS-induced TNF-alpha secretion was significantly reduced in the steroid group, but it increased rapidly during the following days. HLA-DR, ALT, and PT-INR levels were not different between the two groups. The postoperative hospital stay in the steroid group was significantly lower compared to that in the control group (mean, 10.5 days versus 14.8 days; P < 0.05). No differences were found in the convalescence score or postoperative complication rate. CONCLUSIONS: Intravenous methylprednisolone administration before hepatic resection significantly reduced systemic inflammatory cytokine release. No adverse effect on immunity was noted due to the methylprednisolone. We found no significant difference in the convalescence score, but a significantly shorter hospital stay in the steroid group. Further studies with more patients are needed to elucidate the clinical impact of preoperative steroid bolus therapy in liver surgery.