Treatment of peritoneal carcinomatosis using surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC)
Wim P Ceelen, MD, PhD
Tel +32 9332 6251
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.
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 causes are:
- Upper gastrointestinal cancers: stomach, pancreas
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.
Whether you are a candidate for surgery depends on 1. the exact cause (diagnosis, tumour type); 2. the extent of the disease (number and location of peritoneal nodules), and 3. your general condition.
Good indications for surgery / HIPEC are:
- mucinous appendix tumour, with or without pseudomyxoma peritonei
Often, systemic (intravenous) chemotherapy is given during several months before operation. Generally, patients with systemic metastases will not benefit from surgery for PC. Sometimes, small and easily removable liver metastases can be treated at the same time as the peritoneal metastases. Also, patients with large amounts of fluid in the abdomen (ascites), extensive disease on the small bowel, or patients in a much weakened general condition are poor candidates for surgery.
Sometimes, 'preventive' chemoperfusion (HIPEC) is performed in patients who are considered to have a very high risk of developing peritoneal metastases. Examples are perforated colon cancers or patients with colon cancer that is metastatic to the ovaries (Krukenberg tumor).
Patients with carcinomatosis from cancer of the stomach may benefit from debulking/HIPEC on condition that an excellent response is observed after chemotherapy. Most patients will, however, not benefit from surgery. The same is true for patients with cancers of the pancreas or biliary tract.
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’.
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.
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.
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.
Not all patients can be permanently 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, patients may 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. Sometimes, a second or third HIPEC procedure is indicated.
Can I undergo treatment in Ghent University Hospital?
Belgium has a reputation for high standards of healthcare delivery. UZ Ghent is a public, not for profit hospital. Staff at all levels is fluent in French and English. An estimation of the total costs can be obtained from the hospital's administration upon request; this cost depends mainly on the length of stay (average of two weeks).
Can I help?
The department of GI Surgery is actively involved in clinical and experimental research in the field of peritoneal carcinomatosis. Since this is a field in development and the number of patients who benefit from IP chemotherapy is limited compared to those who undergo 'regular' chemotherapy, there is little or no interest from the pharmaceutical industry in this topic. Therefore, financial donations are very welcome in order to support and advance our research. Please contact us when you are interested in making a gift.
© 2013 Department of GI Surgery, Ghent University Hospital