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Clinical Review Criteria

Intraperitoneal Hyperthermic Chemotherapy (IPHC) Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Intraoperative Chemohyperthermic Peritoneal Perfusion (CHPP) Intraperitoneal Hyperthermic Chemoperfusion (IHCP)

Group Health Clinical Review Criteria are developed to assist in administering plan benefits. These criteria neither offer medical advice nor guarantee coverage. Group Health reserves the exclusive right to modify, revoke, suspend or change any or all of these Review Criteria, at Group Health's sole discretion, at any time, with or without notice. Member contracts differ in their benefits. Always consult the patient's Medical Coverage Agreement or call Group Health Customer Service to determine coverage for a specific medical service.


No criteria were developed at this time for Commercial Members. There is insufficient evidence in the published medical literature to show that this service/therapy is as safe as standard services/therapies (and/or) provides better long-term outcomes than current standard services/therapies.

The following information was used in the development of this document and is provided as background only. It is not to be used as coverage criteria. Please only refer to the criteria listed above for coverage determinations.


Hyperthermic intraperitoneal chemotherapy (HIPEC) refers to heated chemotherapy delivered directly to the abdomen. Heat is believed to enhance the cytotoxicity of standard chemotherapy agents, maybe due to increased blood flow, or increased permeability of cell membranes allowing for the diffusion of agents into the tumor nodules at a greater depth. Because patients tolerate elevated intra-abdominal temperatures poorly, treatment can only be performed intraoperatively, under general anesthesia. Therefore, HIPEC can be used as an adjunct to intraoperative chemotherapy, but not with early perioperative or postoperative chemotherapy. A concensus statement was issued in January, 2006 at the International Symposium on Regional Cancer Therapies. The group recommended use of HIPEC, in conjunction with cytoreductive surgery, for treatment of patients with peritoneal surface malignancies of colonic origin (referred to as peritoneal carcinomatosis, PC). PC of colorectal origin is the second-most common cause of death in colorectal cancer. The treatment is not appropriate for patients with distant sites of metastases. Recommendations for HIPEC include the use of mitomycin C (15-35 mg/m2) with a target intraperitoneal temperature of 39-42oC for 60-120 minutes (Esquivel et al., 2006; Verwaal et al., 2003). In addition, HIPEC in conjunction with surgery has also been used to prevent peritoneal carcinomatosis (PC) in high-risk patients, those who have gastric cancer with serosal invasion. Postoperative PC occurs in over half of patients with gastric cancer (Kim & Bae, 2001). There are two types of techniques for HIPEC, open and closed. Both involve intra-abdominal placement of inflow and outflow catheters. With the closed techniques the skin edges are closed, making it easier to maintain a consistent intra-abdominal temperature and reducing the likelihood of chemotherapy spillage. In the open technique, rather than closing the skin edges, the skin is secured to limbs of an abdominal retractor and plastic drapes are sewn to the edges of the skin, acting as a partial barrier. The surgeon can place their hand through the slit in the plastic, and can manipulate

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abdominal contents and assure more even distribution of chemotherapy agent. A disadvantage of the closed technique is a greater chance of release of toxic vapors (Katz & Barone, 2003) . HIPEC does not require FDA approval. The item has not been reviewed previously by MTAC.

Medical Director Clinical Review and Policy Committee

04/16/07 The committee recommended that this service not be covered for Group Health members at this time. There is insufficient evidence of efficacy.

Medical Technology Assessment Committee (MTAC)

Date 04/02/07 Evidence Conclusion Prevention of peritoneal carcinomatosis Two randomized controlled trials from Japan, conducted among patients who underwent surgery for T2-T4 gastric carcinoma with serosal involvement, found a significant benefit from including HIPEC treatment. The study with the stronger methodology (Yonemura et al., 2001) found a higher estimated 5-year survival in the group receiving cytoreduction and HIPEC (61%), compared to two other groups (cytoreduction and normothermic intraperitoneal chemotherapy, 44%; and surgery alone 42%). The other RCT (Fujimoto et al., 1999) had poorly described methodology, and also found a significantly higher estimated survival rate in a group receiving cytoreduction plus HIPEC compared to surgery alone. The first study had a minimum of 2.4 years of follow-up; length of follow-up was not reported in the Fujimoto study. Findings from studies on Japanese gastric cancer may not be generalizable to the United States. Treatment of peritoneal carcinomatosis There is evidence from one reasonably valid randomized controlled trial that HIPEC is beneficial as a treatment for peritoneal carcinomatosis (Verwaal et al., 2003). The study, which included 105 patients with histologically proven peritoneal metastases of colorectal adenocarcinoma, compared an experiemental treatment (cytoreduction and HIPEC, plus adjuvant chemotherapy) to standard treatment (outpatient chemotherapy, surgery only if necessary). After a median follow-up of 22 months, the survival rate was significantly higher in the experimental treatment group (56% vs. 39%). Sub-group analyses suggest that survival was lower in patients with extensive residual disease or involvement of more than 5 regions of the abdominal cavity. A case series by the same research group found an estimated oneyear survival of 75% and three-year survival of 28% with the experimental treatment. There were no long-term survival data for the standard treatment group. The evidence base would be strengthened with additional comparative studies. Outcome The use of intraperitoneal hyperthermic chemotherapy (IPHC) in the treatment of peritoneal carcinomatosis does not meet the Group Health Medical Technology Assessment Criteria.

Evidence/ Source Documents

Date of Literature Search 4/2/2007 Articles Prevention of peritoneal carcinomatosis Three RCTs were identified: all were conducted by Japanese investigators. The two trials with the larger sample sizes (n=139 and n=141) were critically appraised. The third study was smaller (n=82) and had limitations including a non-significant finding with no discussion of statistical power. Citations for the reviewed studies are as follows:

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Yonemura Y, deAretxabala X, Fukimura T et al. Intraoperative chemohyperthermic peritoneal perfusion as a adjuvant to gastric cancer: Final results of a randomized controlled study. Hepato-Gastroenterology 2001; 48: 1776-1782. See Evidence Table Fujimoto S, Takahashi M, Mutou T et al. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. Cancer 1999; 85: 529-534. See Evidence Table Treatment of peritoneal carcinomatosis: One RCT from the Netherlands was identified and critically appraised (Verwaal et al., 2003). There have also been a number of case series, most had sample sizes under 100. The largest case series was a multicenter study by Glehen et al., 2004 and included 506 patients. This study was limited in that it combined data from different centers that had different protocols and patient populations. All of the centers used perioperative intraperitoneal chemotherapy, but it appears that not all used hyperthermic treatment. As a result, the Glehen article was excluded from further review. The next largest case series available in English was by Verwaal et al., 2005. This article reported long-term follow-up on 117 patients, 48 of whom were included in the 2003 RCT, and was critically appraised. The two studies reviewed were as follows: Verwaal VJ, van Ruth S, de Bree E et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003; 21: 3737-3743. See Evidence Table Verwaal VJ, van Ruth S, Witkamp A et al. Long-term survival of peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 2005; 12: 65-71. See Evidence Table

Creation Date 04/19/2007


MTAC Review Date 04/02/2007, 4/16/2007 MDCRPC

Medical Director Clinical Review and Policy Committee

For questions or comments contact: Clinical Criteria Documentation Team

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Clinical Review Criteria: Intraperitoneal Hyperthermic Chemotherapy (IPHC)

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