Isolated Liver and Limb Perfusion in Preclinical and Clinical Studies: gene therapy and biochemotherapeutic strategies

__Abstract__ The liver is the major site of metastatic spread of primary colorectal cancer, whereas 3% of all patients with colorectal cancer will develop resectable liver metastases. If a resection with curative intent is done, a five year survival rate of 25-30% has been demonstrated in a large number of studies. The natural history of untreated patients with comparable liver involvement shows a five year survival rate of 0-3% (8). As noted above, the majority of patients with evidence of liver metastases are irresectable, because of extra-hepatic disease or excessive liver involvement. There is no standard treatment for unresectable hepatic metastases confined to the liver, so novel treatment modalities have to be developed. In order to achieve a better control of intrahepatic disease and to reduce systemic toxicity of the applied therapy, locoregional therapies have been developed. These therapies include hepatic arterial embolization (9), intratumoral injections of ethanol, acetic acid, biological agents, stereotactic or intra-arterial radiotherapy, intralesional laser therapy, cryotherapy, radiofrequency ablation and regional infusion or perfusion of chemotherapeutic drugs

Fifty tumor necrosis factor-based isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors

BACKGROUND: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients, every attempt to avoid an amputation that may end their independence must be considered. METHODS: Out of 306 TNF-based ILPs, 50 ILPs were performed for limb salvage in 43 patients >75 years old (range, 75-91 years): 29 STS and 14 melanoma patients. RESULTS: In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; in the melanoma patients, a 100% response rate and a 93% limb-salvage rate were achieved. Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients. CONCLUSIONS: Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients

Reorganizing the Multidisciplinary Team Meetings in a Tertiary Centre for Gastro-Intestinal Oncology Adds Value to the Internal and Regional Care Pathways. A Mixed Method Evaluation

Introduction: The reorganisation of the structure of a Gastro-Intestinal Oncology Multidisciplinary Team Meeting (GIO-MDTM) in a tertiary centre with three care pathways is evaluated on added value. Methods: In a mixed method investigation, process indicators such as throughput times were analysed and stakeholders were interviewed regarding benefits and drawbacks of the reorganisation and current MDTM functioning. Results: For the hepatobiliary care pathway, the time to treatment plan increased, but the time to start treatment reduced significantly. The percentage of patients treated within the Dutch standard of 63 days increased for the three care pathways. From the interviews, three themes emerged: added value of MDTMs, focus on planning integrated care and awareness of possible improvements. Discussion: The importance of evaluating interventions in oncology care pathways is shown, including detecting unexpected drawbacks. The evaluation provides insight into complex dynamics of the care pathways and contributes with recommendations on functioning of an MDTM. Conclusions: Throughput times are only partly determined by oncology care pathway management, but have influence on the functioning of MDTMs. Process indicator information can help to reflect on integration of care in the region, resulting in an increase of patients treated within the Dutch standard

A Systematic Review and Meta-analysis on Omentoplasty for the Management of Abdominoperineal Defects in Patients Treated for Cancer

Objective: The objective of this systematic review and meta-analysis was to examine the effects of omentoplasty on pelviperineal morbidity following abdominoperineal resection (APR) in patients with cancer. Background: Recent studies have questioned the use of omentoplasty for the prevention of perineal wound complications. Methods: A systematic review of published literature since 2000 on the use of omentoplasty during APR for cancer was undertaken. The authors were requested to share their source patient data. Meta-analyses were conducted using a random-effects model. Results: Fourteen studies comprising 1894 patients (n ¼ 839 omentoplasty) were included. The majority had APR for rectal cancer (87%). Omentoplasty was not significantly associated with the risk of presacral abscess formation in the overall population (RR 1.11; 95% CI 0.79–1.56), nor in planned subgroup analysis (n ¼ 758) of APR with primary perineal closure for nonlocally advanced rectal cancer (RR 1.06; 95% CI 0.68–1.64). No overall differences were found for complicated perineal wound healing within 30 days (RR 1.30; 95% CI 0.92–1.82), chronic perineal sinus (RR 1.08; 95% CI 0.53–2.20), and pelviperineal complication necessitating reoperation (RR 1.06; 95% CI 0.80– 1.42) as well. An increased risk of developing a perineal hernia was found for patients submitted to omentoplasty (RR 1.85; 95% CI 1.26–2.72). Complications related to the omentoplasty were reported in 4.6% (95% CI 2.5%– 8.6%). Conclusions: This meta-analysis revealed no beneficial effect of omentoplasty on presacral abscess formation and perineal wound healing after APR, while it increases the likelihood of developing a perineal hernia. These findings do not support the routine use of omentoplasty in APR for cancer

Back-Table Fluorescence-Guided Imaging for Circumferential Resection Margin Evaluation Using Bevacizumab-800CW in Patients with Locally Advanced Rectal Cancer

Negative circumferential resection margins (CRM) are the cornerstone for the curative treatment of locally advanced rectal cancer (LARC). However, in up to 18.6% of patients, tumor-positive resection margins are detected on histopathology. In this proof-of-concept study, we investigated the feasibility of optical molecular imaging as a tool for evaluating the CRM directly after surgical resection to improve tumor-negative CRM rates. Methods: LARC patients treated with neoadjuvant chemoradiotherapy received an intravenous bolus injection of 4.5 mg of bevacizumab-800CW, a fluorescent tracer targeting vascular endothelial growth factor A, 2-3 d before surgery (ClinicalTrials.gov identifier: NCT01972373). First, for evaluation of the CRM status, back-table fluorescence guided imaging (FGI) of the fresh surgical resection specimens (n = 8) was performed. These results were correlated with histopathology results. Second, for determination of the sensitivity and specificity of bevacizumab-800CW for tumor detection, a mean fluorescence intensity cutoff value was determined from the formalin-fixed tissue slices (n = 42; 17 patients). Local bevacizumab-800CW accumulation was evaluated by fluorescence microscopy. Results: Back-table FGI correctly identified a tumor-positive CRM by high fluorescence intensities in 1 of 2 patients (50%) with a tumor-positive CRM. For the other patient, low fluorescence intensities were shown, although (sub)millimeter tumor deposits were present less than 1 mm from the CRM. FGI correctly identified 5 of 6 tumor-negative CRM (83%). The 1 patient with false-positive findings had a marginal negative CRM of only 1.4 mm. Receiver operating characteristic curve analysis of the fluorescence intensities of formalin-fixed tissue slices yielded an optimal mean fluorescence intensity cutoff value for tumor detection of 5,775 (sensitivity of 96.19% and specificity of 80.39%). Bevacizumab-800CW enabled a clear differentiation between tumor and normal tissue up to a microscopic level, with a tumor-to-background ratio of 4.7 +/- 2.5 (mean SD). Conclusion: In this proof-of-concept study, we showed the potential of back-table FGI for evaluating the CRM status in LARC patients. Optimization of this technique with adaptation of standard operating procedures could change perioperative decision making with regard to extending resections or applying intraoperative radiation therapy in the case of positive CRM

Isolated Hypoxic Hepatic Perfusion with Retrograde Outflow in Patients with Irresectable Liver Metastases; A New Simplified Technique in Isolated Hepatic Perfusion

Background: Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic h

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II)

Background: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. Methods: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3–4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. Discussion: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. Trial registration: clinicaltrials.gov NCT03348150; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing