Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative of clinical circumstances. Therefore, a good preclinical in vivo HIPEC model is needed in which temperature distributions can be well-controlled and are stable throughout treatments. Methods: We designed a setup able to generate and maintain a homogeneous flow during a 90-min HIPEC procedure using our in-house developed treatment planning tools and computer aided design (CAD) techniques. Twelve rats were treated with heated phosphate-buffered saline (PBS) using two catheter setups (one vs. four- inflows) and extensive thermometry. Simulated and measured thermal distribution and core temperatures were evaluated for the different setups. Results: Overall, the four-inflow resulted in more stable and more homogeneous thermal distributions than the one-inflow, with lower standard deviations (0.79 °C vs. 1.41 °C at the outflow, respectively) and less thermal losses. The average thermal loss was 0.4 °C lower for rats treated with the four-inflow setup. Rat core temperatures were kept stable using occasional tail cooling, and rarely exceeded 39 °C. Conclusion: Increasing the number of inflow catheters from one to four resulted in increased flow and temperature homogeneity and stability. Tail cooling is an adequate technique to prevent rats from overheating during 90-min treatments. This validated design can improve accuracy in future in vivo experiments investigating the impact of relevant parameters on the efficacy of different HIPEC protocols.

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482 Background: Patients with T4 or perforated colon cancer are at high risk (~25%) of peritoneal metastases (PM). Sensitivity of imaging modalities for PM is limited and the majority of patients is diagnosed in a palliative setting. This provides a rationale for adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). In this study, the effectiveness of adjuvant HIPEC in reducing the risk of PM was determined. Methods: In this multicenter trial, patients with T4 (either cT4 or pT4, N0-2, M0) or perforated colon cancer, who underwent curative resection were randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy or to adjuvant systemic chemotherapy alone (1:1). Adjuvant HIPEC with oxaliplatin was performed simultaneously (9%) or within five-eight weeks (91%) after the primary tumor resection. Patients without evidence of recurrent disease at 18 months based on CT imaging underwent diagnostic laparoscopy in both arms. The primary endpoint was PM free survival (PMFS) at 18 months using Kaplan Meier analysis. Results: Between April 2015 and January 2017, 204 patients were randomized: 102 in the control arm (0 drop-outs), 102 in the experimental arm (two drop-outs). Surgical exploration at the start of the HIPEC procedure at five-eight weeks postoperatively revealed metastases in 11 patients (PM in 9/11) in the experimental arm, and adjuvant HIPEC was not applied. Adjuvant systemic chemotherapy was administered in 89/100 eligible patients after median 6 weeks (IQR 5-7) in the control arm and in 84/89 after 10 weeks (IQR 9-12) in the experimental arm. PM rate after completion of 18 months follow-up was 22/102 and 18/100, respectively. In the ITT analysis no difference in 18 months PMFS was observed: 77% (control) versus 81% (experimental), HR 0.836 (0.489-1.428)). Also, no differences were observed in 18 months DFS (HR 1.016 (0.646-1.598)) and OS (HR 1.139 (0.532-2.439)). One patient developed encapsulating peritoneal sclerosis after HIPEC. Conclusions: Adjuvant HIPEC with oxaliplatin for patients with T4 or perforated colon cancer does not result in improved 18 months PMFS. Long-term results have to be awaited to assess the role of HIPEC in the adjuvant setting. Clinical trial information: NCT02231086.