1 2 3 7 4 8 6 9 131 10 11 12 13 MATERIALS AND METHODS Animal Model of Peritoneal Carcinomatosis 6 14 Operative Procedure 2 2 11 Subsequently, CS, including a routine omentectomy, was performed in all rats. Irresectable tumor deposits were cauterized using an electrocoagulation device. After completion of the surgical cytoreduction, the abdominal wall was closed in two layers using continuous Vicryl 3/0 sutures for the muscular component and iron wound clips for the skin in animal treated with CS only or CS + RIT. Monoclonal Antibody, Radiolabeling, and RIT 15 177 11 177 177 177 177 177 16 Mitomycin-C Mitomycin-C (MMC) was obtained from Nycomed Christiaens BV (Breda, The Netherlands) as a powder in glass vial (40 mg/vial). Immediately before use, MMC was dissolved in 0.9% sodium chloride to the appropriate concentrations. HIPEC Procedure 1 FIG. 1. HIPEC Perfusion System; MMC Mitomycin C Kyowa 16 mg/L perfusate. Adapted from Ref. 19. Reproduced with permission.  Intraperitoneal Distribution of MMC and Dose Determination Prior to the therapy experiment with HIPEC, we investigated the intraperitoneal distribution of the perfusion fluid using a methylene blue stained perfusate. The perfusate was administered in the same fashion as in the therapeutic experiment. After completion, the abdominal cavity was inspected for the presence of blue dye in all quadrants on both parietal as well as visceral peritoneum of the intra-abdominal organs and the diaphragm. Subsequently, a study to determine the dose of MMC that resulted in acceptable toxicity was performed in nine animals (three animals per group). Animals underwent a laparotomy including an omentectomy and complete bowel inspection followed by heated perfusion of the abdominal cavity with MMC at 4 mg/L or 16 mg/L. Control rats underwent laparotomy and an omentectomy only. Body weight and physical condition were monitored during 6 days following the procedure to assess treatment-related toxicity. Treatment Efficacy 6 Follow-Up 2 2 Statistical Analysis P RESULTS Intraperitoneal Distribution of HIPEC and Dose Determination 2 FIG. 2. Intraperitoneal distribution of methylene blue stained perfusate.  3 FIG. 3. The relative body weight of Wag/Rij rats after exploratory laparotomy (control) and heated intraperitoneal chemotherapy (HIPEC) given immediately postoperatively in different doses. Data represent means ± standard error of the mean (SEM).  Operative Procedure P 1 P TABLE 1. Treatment group characteristics  PCI Median (range) CS CS + HIPEC CS + RIT Preoperative body weight (g) 266 (251–287) 264 (245–285) 262 (244–276) Tumor score per site   Greater omentum 2 (2–3) 2 (1–2) 2 (1–2)   Liver hilum 1 (0–1) 1 (0–1) 1 (0–1)   Perisplenic 0 (0–1) 0 (0) 0 (0)   Mesentery 1 (0–2) 1 (0–2) 1 (0–2)   Gonadal fatpads 0 (0–2) 0 (0–2) 1 (0–2)   Diaphragm 0 (0–1) 0 (1) 0 (0–1)   Parietal peritoneum 1 (0–1) 1 (0–1) 1 (0–1) Total 5 (4–8) 5 (4–6) 5 (4–8) Resection macroscopically complete   Yes 12 13 13   No 3 2 2 Treatment group characteristics (peritoneal cancer index; PCI) found during laparotomy before the administration of the adjuvant therapy. CS, cytoreductive surgery; HIPEC, heated intraperitoneal chemotherapy; RIT, radioimmunotherapy. PCI is expressed as median and range. 4 FIG. 4. The recorded intra-abdominal and rectal temperature during the HIPEC procedure. Data represent means ± standard error of the mean (SEM).  5 P P P FIG. 5. The relative body weight of Wag/Rij rats with small peritoneal CC-531 tumors in the first 14 days after cytoreductive surgery (CS) only, CS + radioimmunotherapy given immediately postoperatively (RIT) or heated intraperitoneal chemotherapy (HIPEC) given immediately postoperatively. Data represent means ± standard error of the mean (SEM).  Treatment Efficacy P P 6 P P P FIG. 6. Kaplan–Meier survival curves for Wag/Rij rats with small peritoneal CC-531 tumors after cytoreductive surgery (CS), CS + RIT (RIT) or CS + HIPEC (HIPEC).  At the endpoint of the study, 16 weeks after CS, 14 animals (two animals in the CS group, five animals in the CS + HIPEC group, and seven animals in the CS + RIT group) were still alive, without any physical signs of intraperitoneal tumor growth. Of these 14 animals that were still alive 16 weeks after surgery, one animal in the CS + HIPEC group and three animals in the CS + RIT group showed macroscopic evidence of tumor at dissection. In the remaining 10 animals (two in the CS alone group, four in the HIPEC group, and four in the RIT group) not even microscopic tumor presence was found. DISCUSSION In the present study, adjuvant radioimmunotherapy after cytoreductive surgery for peritoneal carcinomatosis of colorectal origin in rats significantly improved survival, whereas HIPEC did not. In addition, the application of HIPEC was associated with considerably more toxicity as compared to RIT. 14 12 13 17 11 15 177 177 11 16 18 19 22 19 23 12 12 24 25 19 22 19 6 26 177 11 16 111 11 27 6 13 131 10 17 177 177 11 16 Our study therefore justifies the consideration of intraperitoneal radioimmunotherapy after cytoreductive surgery in case of peritoneal carcinomatosis of colorectal cancer. In clinical studies, this approach should be compared with HIPEC. CONCLUSION This study showed that RIT adjuvant to CS significantly improved survival compared to CS alone in a rat model of PC of CRC, whereas the contemporary gold standard, HIPEC, did not cause a significant improvement in survival. This improvement of survival was associated with a decreased level of treatment-related toxicity compared with HIPEC. Adjuvant radioimmunotherapy might therefore be an alternative adjuvant treatment after cytoreductive surgery of PC of colorectal origin in a clinical trial setting.