Toxicity and complications


The added toxicity of hyperthermic perfusion combined with extensive surgery results in a considerable morbidity and mortality risk, and this has to be carefully weighed against any possible benefit of the procedure in every elegible patient. Mortality ranges from 4-8% in the various papers, with a morbidity rate ranging from 20%-35%. It is probable, that the postoperative complication rate mainly depends upon the extent of the procedure. Although minor side effects such as prolonged paralytic ileus is a concern, systemic or local toxicity of the chemotherapy itself is usually limited although severe abdominal pain or bone marrow depression can occur. I a review of 200 patients by Stephens et al, the postoperative complication rate was associated with the extent of surgery and not to variables related to the administration of chemohyperthermia. (1)
A similar conclusion was proposed by Glehen et al, who found duration of surgery and carcinomatosis stage to be the most common predictors of morbidity in an analysis of 217 HIPEC procedures. (2)
Others have, however, noted increased morbidity and mortality with rising intraabdominal target temperature.(3)

One of the main causes of postoperative serious morbidity following HIPEC is the occurrence of an anastomotic leak. The incidence of a digestive fistula was 15% in the randomized trial by Verwaal and 8.3% in the meta-analysis by Glehen. Most patients will have at least 1 bowel anastomosis performed, and the effects of chemohyperthermia on anastomotic healing are therefore important to note. Intestinal anastomoses are usually constructed after the perfusion in order to facilitate uniform distribution of heat and drug. In animal studies, anastomotic healing is impaired following intraperitoneal mitomycin C, but not following 5-fluorouracil at normal temperature. (4, 5)
Local hyperthermia in itself has no adverse effects on rat anastomotic healing.(6)
When combined with preoperative irradiation, however, hyperthermia increases anastomotic complications in a rat model. (7)

Even at moderate temperatures, HIPEC during 90 minutes invariabely causes edema of the small bowel wall. In order to avoid anastomotic leaks, it is therefore probably safer to construct small bowel anastomoses before the perfusion starts.

  1. Stephens AD, Alderman R, Chang D, Edwards GD, Esquivel J, Sebbag G/, et al./ Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the Coliseum technique/./ /Annals of Surgical Oncology /1999; *6*: 790-6.
  2. Glehen O, Osinsky D, Cotte E, Kwiatkowski F, Freyer G, Isaac S/, et al./ Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinornatosis: Morbidity and mortality analysis of 216 consecutive procedures/./ /Annals of Surgical Oncology /2003; *10*: 863-9.
  3. Jacquet P, Stephens AD, Averbach AM, Chang D, Ettinghausen SE, Dalton RR/, et al./ Analysis of morbidity and mortality in 60 patients with peritoneal carcinomatosis treated by cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy/./ /Cancer /1996; *77*: 2622-9.
  4. Fumagalli U, Trabucchi E, Soligo M, Rosati R, Rebuffat C, Tonelli C/, et al./ Effects of Intraperitoneal Chemotherapy on Anastomotic Healing in the Rat/./ /Journal of Surgical Research /1991; *50*: 82-7.
  5. Kuzu MA, Koksoy C, Kale T, Demirpence E, and Renda N. Experimental study of the effect of preoperative 5-fluorouracil on the integrity of colonic anastomoses/./ /British Journal of Surgery /1998; *85*: 236-9.
  6. Shimizu T, Maeta M, and Koga S. Influence of Local Hyperthermia on the Healing of Small Intestinal Anastomoses in the Rat/./ /British Journal of Surgery /1991; *78*: 57-9.
  7. Biert J, Seifert W, deMan B, Wobbes T, Hoogenhout J, and Hendriks T. Combined preoperative irradiation and local hyperthermia delays early healing of experimental colonic anastomoses/./ /Archives of Surgery /1996; *131*: 1037-42.