Hyperthermic intraperitoneal chemotherapy with mitomycin C and 5‑fluorouracil in patients at high risk of peritoneal metastasis from colorectal cancer: A preliminary clinical study

Shimizu,Tomoharu; Murata,Satoshi; Sonoda,Hiromichi; Mekata,Eiji; Ohta,Hiroyuki; Takebayashi,Katsushi; Miyake,Tohru; Tani,Tohru

doi:10.3892/mco.2014.244

Hyperthermic intraperitoneal chemotherapy with mitomycin C and 5‑fluorouracil in patients at high risk of peritoneal metastasis from colorectal cancer: A preliminary clinical study

Authors:
- Tomoharu Shimizu
- Satoshi Murata
- Hiromichi Sonoda
- Eiji Mekata
- Hiroyuki Ohta
- Katsushi Takebayashi
- Tohru Miyake
- Tohru Tani
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Affiliations: Department of Surgery, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan
Published online on: January 16, 2014 https://doi.org/10.3892/mco.2014.244
Pages: 399-404

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Abstract

Although hyperthermic intraperitoneal chemotherapy (HIPEC) has been extensively used to treat patients with peritoneal metastases (PM) from colorectal cancer (CRC), a standard protocol has not yet been established. The aim of this preliminary clinical study was to confirm in vitro the efficacy of mitomycin C combined with 5‑fluorouracil (MMC‑5FU) under hyperthermic conditions in CRC and investigate the pharmacokinetics and feasibility of HIPEC with MMC‑5FU for patients at high risk of PM from CRC. To simulate HIPEC in vitro, we used the collagen gel droplet‑embedded culture drug sensitivity test with the HCT166 colorectal cell line to assess the antitumor efficacy of MMC and 5FU as single‑agent and combination treatments following incubation with HCT116 cells for 30 min at either 37 or 42˚C. In addition, five patients at high risk of PM from CRC underwent surgical tumor resection followed by HIPEC with MMC‑5FU. Our results demonstrated that the combined administration of MMC‑5FU suppressed tumor cell proliferation more efficiently compared to either agent used alone. In addition, hyperthermia at 42˚C significantly enhanced drug sensitivity. During the clinical application of HIPEC with MMC‑5FU, no grade 4 hematological toxicities or surgical adverse events were recorded. In addition, there was no evidence of peritoneal recurrence during a median observational period of 38 months. Of note, two patients with positive intraoperative peritoneal cytology at the first surgery developed no peritoneal recurrence and exhibited negative peritoneal cytology at the second surgery. In conclusion, HIPEC using MMC‑5FU was shown to be a feasible therapeutic option, with an acceptable toxicity profile, for patients at high risk of PM from CRC. Therefore, HIPEC with MMC‑5FU may be a promising novel therapeutic option for such patients, which merits further verification of its safety and efficacy in large‑scale clinical trials.

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1.	Stewart JH IV, Shen P and Levine EA: Intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: current status and future directions. Ann Surg Oncol. 12:765–777. 2005. View Article : Google Scholar
2.	Chua TC, Esquivel J, Pelz JO and Morris DL: Summary of current therapeutic options for peritoneal metastases from colorectal cancer. J Surg Oncol. 107:566–573. 2013. View Article : Google Scholar : PubMed/NCBI
3.	Mohr Z, Hirche C, Liebeskind U, Rau B and Hunerbein M: Feasibility of delayed hyperthermic intraperitoneal chemotherapy in case of unforeseen complications. Eur Surg Res. 47:19–25. 2011. View Article : Google Scholar : PubMed/NCBI
4.	Yonemura Y, Elnemr A, Endou Y, et al: Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer. World J Gastrointest Oncol. 2:85–97. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Imano M, Imamoto H, Itoh T, et al: Impact of intraperitoneal chemotherapy after gastrectomy with positive cytological findings in peritoneal washings. Eur Surg Res. 47:254–259. 2011. View Article : Google Scholar : PubMed/NCBI
6.	Fujishima Y, Goi T, Kimura Y, Hirono Y, Katayama K and Yamaguchi A: MUC2 protein expression status is useful in assessing the effects of hyperthermic intraperitoneal chemotherapy for peritoneal dissemination of colon cancer. Int J Oncol. 40:960–964. 2012.
7.	Bosanquet DC, Harris DA, Evans MD and Beynon J: Systematic review and meta-analysis of intraoperative peritoneal lavage for colorectal cancer staging. Br J Surg. 100:853–862. 2013. View Article : Google Scholar
8.	Mohan HM, O’Connor DB, O’Riordan JM and Winter DC: Prognostic significance of detection of microscopic peritoneal disease in colorectal cancer: a systematic review. Surg Oncol. 22:e1–e6. 2013. View Article : Google Scholar : PubMed/NCBI
9.	Glockzin G, Rochon J, Arnold D, et al: A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial. BMC Cancer. 13:672013. View Article : Google Scholar
10.	Koppe MJ, Boerman OC, Oyen WJ and Bleichrodt RP: Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg. 243:212–222. 2006. View Article : Google Scholar : PubMed/NCBI
11.	Klaver YL, Hendriks T, Lomme RM, Rutten HJ, Bleichrodt RP and de Hingh IH: Intraoperative versus early postoperative intraperitoneal chemotherapy after cytoreduction for colorectal peritoneal carcinomatosis: an experimental study. Ann Surg Oncol. 19(Suppl 3): S475–S482. 2012. View Article : Google Scholar
12.	Weber T, Roitman M and Link KH: Current status of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer. Clin Colorectal Cancer. 11:167–176. 2012. View Article : Google Scholar
13.	Kobayashi H, Tanisaka K, Doi O, et al: An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures. Int J Oncol. 11:449–455. 1997.
14.	Okumura K, Shiomi H, Mekata E, et al: Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer. Oncol Rep. 15:875–882. 2006.
15.	Muller M, Cherel M, Dupre PF, Gouard S, Collet M and Classe JM: The cytotoxic effect of combined hyperthermia and taxane chemotherapy on ovarian cancer cells: results of an in vitro study. Eur Surg Res. 48:55–63. 2012. View Article : Google Scholar : PubMed/NCBI
16.	Sugarbaker PH: Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and treatment of peritoneal carcinomatosis and sarcomatosis. Semin Surg Oncol. 14:254–261. 1998. View Article : Google Scholar : PubMed/NCBI
17.	Kuzuya T, Yamauchi M, Ito A, Hasegawa M, Hasegawa T and Nabeshima T: Pharmacokinetic characteristics of 5-fluorouracil and mitomycin C in intraperitoneal chemotherapy. J Pharm Pharmacol. 46:685–689. 1994. View Article : Google Scholar : PubMed/NCBI
18.	Pestieau SR, Marchettini P, Stuart OA, Chang D and Sugarbaker PH: Prevention of intraperitoneal adhesions by intraperitoneal lavage and intraperitoneal 5-fluorouracil: experimental studies. Int Surg. 87:195–200. 2002.PubMed/NCBI
19.	Sugarbaker PH and Jablonski KA: Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 221:124–132. 1995. View Article : Google Scholar
20.	Sugarbaker PH: Cytoreductive surgery plus hyperthermic perioperative chemotherapy for selected patients with peritoneal metastases from colorectal cancer: a new standard of care or an experimental approach? Gastroenterol Res Pract. 2012:3094172012. View Article : Google Scholar
21.	Wyatt MD and Wilson DM III: Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci. 66:788–799. 2009. View Article : Google Scholar : PubMed/NCBI
22.	De Roover A, Detroz B, Detry O, et al: Adjuvant hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) associated with curative surgery for locally advanced gastric carcinoma. An initial experience. Acta Chir Belg. 106:297–301. 2006.
23.	Tentes AA, Spiliotis ID, Korakianitis OS, Vaxevanidou A and Kyziridis D: Adjuvant perioperative intraperitoneal chemotherapy in locally advanced colorectal carcinoma: preliminary results. ISRN Surg. 2011:5298762011. View Article : Google Scholar
24.	Raue W, Tsilimparis N, Bloch A, Menenakos C and Hartmann J: Volume therapy and cardiocircular function during hyperthermic intraperitoneal chemotherapy. Eur Surg Res. 43:365–372. 2009. View Article : Google Scholar : PubMed/NCBI
25.	Mizumoto A, Canbay E, Hirano M, et al: Morbidity and mortality outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at a single institution in Japan. Gastroenterol Res Pract. 2012:8364252012. View Article : Google Scholar : PubMed/NCBI