Treatment of peritoneal carcinomatosis using surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) WP Ceelen, MD, PhD
Overview What is ‘peritoneal carcinomatosis’? What is ‘peritoneal carcinomatosis’? Peritoneal carcinomatosis (PC) is a form of cancer that is characterized by widespread implantation of tumor nodules inside the abdomen (belly). These nodules are attached on a thin tissue layer that covers the inside of the abdomen and also the organs inside. This tissue layer is called the peritoneum, and is made of 1 layer of flat rounded cells: the mesothelial cells. Usually, PC is a late disease manifestation of various digestive or gynecological cancers and often is associated with organ metastasis in the liver, lungs, or bone. Peritoneal carcinomatosis is caused by shedding of loose cells from the main tumor mass. These cells are transported inside the abdomen and attach on the peritoneal surface. Certain sites in the abdomen are more prone to implantation of cancer cells: the pelvis, the greater omentum, and the peritoneum covering the diaphragm. Which cancers cause peritoneal carcinomatosis? In most patients with PC, the primary tumor is located in the digestive system or in the ovary. In rare cases, PC can be caused by a primary tumor outside the abdomen such as melanoma or lobular breast cancer. The most frequent locations are: Upper gastrointestinal cancers: stomach, pancreas What is ‘pseudomyxoma peritonei’? Tumors of the appendix are rare, but usually have a better prognosis than cancer of the large bowel. Several histological (microscopic) types can be found, and depending on the exact type the disease will be more or less aggressive. Aggressive appendiceal cancers show signs of proliferation (cell division) and invasiveness (cancer spread to local lymph nodes and distant organs). On the other end of the spectrum are appendiceal tumors that hardly produce any cells, but large amounts of mucus or slime that slowly fills the entire abdomen. This form is often called ‘pseudomyxoma peritonei’ or PMP, a term that is purely descriptive and does not represent a well defined disease. What treatments are available for peritoneal carcinomatosis? The therapeutic options depend on the tumor type, and on the extent
of the disease. Generally, patients with systemic metastases will not
benefit from surgery for PC. Also, patients with large amounts of fluid
in the abdomen (ascites) or in a much weakened general condition are
poor candidates for surgery. How is surgery for peritoneal carcinomatosis performed? The procedure involves removal or stripping of the affected peritoneum from the underlying tissue; this procedure is called a ‘peritonectomy’. Depending on the extent of the disease, one or more abdominal regions will be treated. Also, since the peritoneum covers the abdominal organs, it often is necessary the remove parts of the small bowel, large bowel, or stomach. The greater omentum is nearly always involved and has to be removed. The complete procedure is sometimes called ‘debulking’ or ‘cytoreduction’.
Peritonectomy of the left upper abdomen. The peritoneal layer containing tumor nodules is stripped from the underlying diaphragmatic muscle. Source: Sugarbaker PH. (2003) Peritonectomy procedures. Surg Oncol Clin N Am 12:703-727
Image of the left upper abdomen after completion of peritonectomy showing spleen, stomach, and diaphragmatic muscle.
What are the advantages to administer intraperitoneal (IP) chemotherapy during surgery? The reasons to administer IP chemotherapy can be summarized as follows. First, IP delivery allows to give a much higher dose of chemotherapy because the barrier function of the abdominal wall limits the amount of drug that enters the bloodstream. Higher doses result in a high local drug concentration and therefore a better tumor killing effect. Second, administration during surgery allows uniform distribution of the drug resulting in adequate treatment of all abdominal regions. This is far more difficult when drug is instilled using a catheter after the procedure, when adhesions prevent access of the drug to all abdominal recesses and cavities. Ultimately, IP chemotherapy aims to kill loose tumor cells that could remain after surgery. What types of chemotherapy are used for IP therapy? The choice of chemotherapy depends on the tumor type and on specific properties of the drug such as cell cycle specificity, water solubility, thermal enhancement, and local toxicity. The best studied agents for IP administration are the platinum compounds (cisplatin, oxaliplatin, carboplatin), that are active against a variety of cancer types. Other drugs used for IP therapy include paclitaxel (Taxol), mitomycin C, doxorubicin, and irinotecan.
Chemotherapeutic agents used for hyperthermic intraperitoneal chemoperfusion. MW, molecular weight; AUC, area under the concentration over time curve; TE, thermal enhancement; NA, not available
Hyperthermia means that the chemotherapy is heated to a temperature
above 40°C. The reason to heat chemotherapy is twofold: first, hyperthermia
as such is toxic for cancer cells, but far less so for normal cells.
Second, many chemotherapy drugs have been shown to be more active when
combined with hyperthermia. When a heated solution is given in the abdomen,
the temperature rapidly falls because heat is transported away with
the bloodstream. Therefore, the solution has to be continuously heated
to compensate for the cooling effect of the blood perfusion in the abdomen.
This is done by creating a perfusion circuit, consisting of inflow and
outflow tubes, a roller pump, and a heat exchanger. Fluid leaves the
abdomen, is heated, and returned into the abdomen by the action of the
roller pump. This system is very similar to an extracorporeal blood
circulation circuit used during cardiac surgery. Depending on the type
of chemotherapy, the perfusion lasts from 30 to 90 minutes. The target
temperature during chemoperfusion varies between centers, and can range
from 41°C to 43°C. The temperature is continuously monitored
inside the abdomen by several temperature probes.
Setup during closed abdomen chemoperfusion showing inflow and outflow drains, roller pump, and temperature measurement apparatus
Setup during open perfusion ('coliseum technique). The abdomen is covered with a plastic hood to protect the operatign room environment during chemoperfusion.
Postoperative morbidity and mortality are related to the extent of surgery. In experienced centers, the risk of mortality is lower than 2% while significant complications develop in less than 30% of patients. The most common complications are caused by infection: anastomotic leak with peritonitis, pneumonia, or other severe infections. The chemotherapy usually does not cause significant complications because blood levels of the drug remain very low. Hyperthermia can cause a prolonged paralysis of the stomach and bowel (‘ileus’), which can result in the need to keep the nasogastric tube during several days. Most patients will not be cured by surgery and HIPEC. The aim of the procedure is to provide a prolongation of the patient’s life expectancy while preserving the overall quality of life. The amount of survival time gained depends primarily on the type of cancer, and also on the completeness of surgical removal. After complete resection of pseudomyxoma peritonei, many patients will survive many years (often >10) without signs of recurrence. In patients with colorectal cancer, surgery with HIPEC was shown to double survival time compared to chemotherapy alone. Also, with the availability of more active and molecular systemic anticancer drugs, many cancer types are turned from a rapidly fatal disease into a chronic disease, where judicious use of surgery and/or systemic therapy including chemotherapy, molecular therapy, or radiotherapy allows prolonged survival with a good quality of life. Individual therapy decisions should always be the result of multidiscipliary evaluation. General medicalinformation on surgery and HIPEC 1 General medical information on surgery and HIPEC 2 Book on peritoneal carcinomatosis (Springer 2007) Pseudomyxoma peritonei support site Pseudomyxoma awareness organization
© 2008 Department of GI Surgery, Ghent University Hospital
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