KEY WORDSColorectal metastases, liver metastases, unresectable metastases, adjuvant chemotherapy, intraarterial chemotherapy, hepatic arterial infusion pump chemotherapy BACKGROUNDOver the past several years, important progress has been made in the treatment of patients with metastatic colorectal cancer. Median overall survival in these patients now extends beyond 2 years with a combination of modern systemic therapies [1][2][3][4][5][6][7][8] . Approximately 60% of patients present with liver-only or liver-predominant metastases, and if complete surgical resection is achieved in those patients, 5-year overall survival approaches 50% 9-11 . In patients with initially unresectable colorectal liver metastases (crlms), systemic therapy can, in up to 30% of patients, produce a tumour response sufficient to allow for resection and the possibility of long-term survival or cure 12,13 . An important goal of aggressive therapy in patients with initially unresectable crlms is therefore conversion to resectability.Although the response rate to systemic therapy is good in untreated patients, response rates to chemotherapy in the second-line setting remain disappointing. The most encouraging results are obtained with the addition of biologic agents to chemotherapy, achieving response rates of up to 20%-35% and a corresponding median survival of up to 1 year in the second-line setting [14][15][16][17][18] . Given the limited efficacy of systemic therapy beyond the first-line setting, patients could benefit from other treatments that would increase response and resectability rates.Hepatic arterial infusion pump (haip) chemotherapy has been extensively studied in patients with crlms. The rationale for arterial delivery of ABSTRACT Despite significant improvements in systemic therapy for patients with colorectal liver metastases (crlms), response rates in the first-line setting are not optimal, and response rates in the second-line setting remain disappointing. Hepatic arterial infusion pump (haip) chemotherapy has been extensively studied in patients with crlms, but it remains infrequently used.We convened an expert panel to discuss the role of haip in the contemporary management of patients with crlm. Using a consensus process, we developed these statements:• haip chemotherapy should be given in combination with systemic chemotherapy.• haip chemotherapy should be offered in the context of a multidisciplinary program that includes expertise in hepatobiliary surgery, medical oncology, interventional radiology, nursing, and nuclear medicine.• haip chemotherapy in combination with systemic therapy should be considered in patients with unresectable crlms who have progressed on first-line systemic treatment. In addition, haip chemotherapy is acceptable as first-line treatment in patients with unresectable colorectal liver metastases.• haip chemotherapy is not recommended in the setting of extrahepatic disease outside the context of a clinical trial.• haip chemotherapy in combination with systemic therapy is an option for select pati...

Concurrent administration of sodium thiosulfate (STS) can protect against the nephrotoxic effects of even very-high-dose cisplatin (CDDP) (i.e., 270 mg/m2 given intraperitoneally). The effect of STS on the pharmacology and toxicity of CDDP was investigated in patients receiving at each treatment 90 mg of CDDP/m2 intraperitoneally, with STS given concurrently on alternate cycles by the intravenous route. The patients received a total of 38 courses of therapy, 21 without STS and 17 with STS. STS reduced the total exposure to diethyldithiocarbamate-reactive CDDP for the peritoneal cavity and plasma by 36% and 25%, respectively. When given alone, CDDP caused a statistically significant acute reduction in creatinine clearance levels; this reduction was less evident when STS was given. We conclude that, whereas STS does reduce systemic exposure, the magnitude of this effect was not sufficient to account for the ability of STS to protect against high-dose CDDP.

Twenty-one patients with malignant mesothelioma were treated with an experimental intracavitary chemotherapy regimen of weekly intraperitoneal or intrapleural cisplatin (90-100 mg/m2) with simultaneous intravenous sodium thiosulfate delivered to protect against cisplatin-induced nephrotoxicity. One of eight patients (12.5%) receiving intrapleural therapy and nine of 13 patients receiving intraperitoneal therapy demonstrated objective evidence of a clinical response, including three surgically defined major tumor regressions (23%). Patients receiving intrapleural treatment had more advanced disease prior to therapy than those receiving intraperitoneal therapy. It was concluded that intraperitoneal cisplatin is an active treatment program for intra-abdominally localized mesothelioma. Additional investigation of intrapleural cisplatin should be undertaken in a patient population with less advanced disease or following surgical debulking.

Ninety ovarian carcinoma patients failing primary intravenous (IV) combination chemotherapy were treated with cisplatin-based combination intraperitoneal therapy. Sixty-five patients had residual disease greater than 2 cm at the start of intraperitoneal therapy. Their median survival was 8 months. Twenty-five patients had disease less than 2 cm; their median survival was greater than 49 months, and the survival curve has an apparent plateau at 69%, with no relapses having occurred after 32 months. The median survival for all 90 patients was 15 months. The median duration of follow-up for all patients was 37 months. These results confirm the critical role of tumor bulk in determining the effectiveness of intraperitoneal therapy, and suggest a role for intraperitoneal salvage treatment in patients with small-volume disease.

Background: Lifestyle interventions have been shown to delay or prevent the onset of type 2 diabetes among high risk adults. A better understanding of the variability in physiological responses would support the matching of individuals with the best type of intervention in future prevention programmes, in order to optimize risk reduction. The purpose of this study was to determine if phenotypic characteristics at baseline or following a 12 weeks lifestyle intervention could explain the inter-individual variability in change in glucose tolerance in individuals with high risk for type 2 diabetes. Methods: In total, 285 subjects with normal glucose tolerance (NGT, FINDRISC score > 12), impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were recruited for a 12 weeks lifestyle intervention. Glucose tolerance, insulin sensitivity, anthropometric characteristics and aerobic fitness were measured. Variability of responses was examined by grouping participants by baseline glycemic status, by cluster analysis based on the change in glucose tolerance and by Principal Component Analysis (PCA). Results: In agreement with other studies, the mean response to the 12 weeks intervention was positive for the majority of parameters. Overall, 89% improved BMI, 80% waist circumference, and 81% body fat while only 64% improved fasting plasma glucose and 60% 2 h glucose. The impact of the intervention by glycaemic group did not show any phenotypic differences in response between NGT, IFG, and IGT. A hierarchical cluster analysis of change in glucose tolerance identified four sub-groups of “responders” (high and moderate) and “non-responders” (no response or deteriorated) but there were few differences in baseline clincal and physiological parameters or in response to the intervention to explain the overall variance. A further PCA analysis of 19 clinical and physiological univariables could explain less than half (48%) of total variability. Conclusion: We found that phenotypic characteristics from standard clinical and physiological parameters were not sufficient to account for the inter-individual variability in glucose tolerance following a 12 weeks lifestyle intervention in inidivuals at high risk for type 2 diabetes. Further work is required to identify biomarkers that complement phenotypic traits and better predict the response to glucose tolerance.