Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. Methods/Design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. Trial registration number: NCT02231086 (Clinicaltrials.gov)

High plasma tumor necrosis factor (TNF)-α concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-α, interferon-γ, and melphalan

Objectives: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-α and melphalan after pretreatment with recombinant interferon-γ as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-α concentrations and relate these values with indices of disease severity. Setting: A 12-bed surgical intensive care unit (ICU) in a university referral hospital. Design: Prospective, descriptive study. Patients: Consecutive patients (n = 25) treated with hyperthermic isolated limb perfusion. Interventions: Blood samples were taken at regular intervals to determine TNF-α concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-α. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter. Measurements and Main Results: All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-α concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-α, no patient died in the ICU, although the patient with the highest TNF-α concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-α concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05). Conclusions: Hyperthermic isolated limb perfusion with recombinant TNF-α leads to high systemic concentrations of TNF-α, probably due to leakage of recombinant TNF-α from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-α, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients

Effects of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor α and melphalan on the human fibrinolytic system

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor α (r-TNF-α) and melphalan, with or without pretreatment with recombinant IFN-γ (r-IFN-γ). Twenty patients were treated with r-TNF- α and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-α and melphalan, eight received r-IFN-γ for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-α from lite perfusion circuit to the systemic circulation was observed in all r-TNF-α-treated patients (mean maximum TNF-α, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-α-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 μg/liter in 22 h, respectively). No additional effect of IFN-γ pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-α and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-α from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of micro-thrombi in the systemic circulation

Effects of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor α and melphalan on the human fibrinolytic system

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor α (r-TNF-α) and melphalan, with or without pretreatment with recombinant IFN-γ (r-IFN-γ). Twenty patients were treated with r-TNF- α and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-α and melphalan, eight received r-IFN-γ for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-α from lite perfusion circuit to the systemic circulation was observed in all r-TNF-α-treated patients (mean maximum TNF-α, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-α-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 μg/liter in 22 h, respectively). No additional effect of IFN-γ pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-α and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-α from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of micro-thrombi in the systemic circulation

Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide.

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