Chemotherapy


Principles of intraperitoneal chemotherapy
  1. dose - response relationship

    Intraperitoneal application of drugs such as cytostatic agents will lead to high local drug concentrations in the abdominal cavity. Due to the existence of a dose - response - relationship for cytostatic agants such increase in local drug concentrations will lead to an increase in response rates.


  2. peritoneal plasma barrier

    Large molecular weight compounds when instilled into the peritoneal cavity are sequestered at that site for long periods. The physiologic barrier to the release of intraperitoneal drugs is called the peritoneal space to plasma barrier. This means that the exposure of peritoneal surfaces to pharmacologically active molecules can be increased considerably by giving the drugs via the intraperitoneal as opposed to intravenous route.
Benefits of intraoperative chemotherapy
  • Intraoperative chemotherapy allows a uniform distribution of drugs to all surfaces of the abdomen and pelvis.
  • Nausea and vomiting are avoided because the patient is under general anesthesia.
Limits of intraperitoneal chemotherapy

Intracavitary instillation allows very limited penetration of drug into tumor nodules. Only the outermost layer (~1 mm) of a cancer nodule is penetrated by the chemotherapy. This means that only minute tumor nodules can be definitively treated. Microscopic residual disease is the ideal target for intraperitoneal chemotherapy protocols.

A second cause for limited success with intraperitoneal chemotherapy is a non-uniform drug distribution. A majority of patients treated by drug instillation into the abdomen or pelvis had prior surgery, which invariably causes scarring between peritoneal surfaces. The adhesions create multiple barriers to the free access of fluid. Although the instillation of a large volume of fluid will partially overcome the problems created by adhesions, some surface areas will have no access to chemotherapy. Limited access from adhesions was impossible to predict and increased with repeated instillations of chemotherapy solutions.

Only an intraoperative use of intraperitoneal chemotherapy can overcome the problem of non-uniform distribution.

Tumor Cell Entrapement

The ´tumor cell entrapment´ hypothesis explains the inevitable progression of malignancy in patients who undergo treatment of peritoneal surface cancer using surgery alone. This theory relates the high incidence and rapid progression of peritoneal surface implantation to
  1. free intraperitoneal tumor emboli,
  2. fibrin entrapment of intra-abdominal tumor emboli on traumatized peritoneal surfaces
  3. blood clots that remain in the abdomen or pelvis that contain viable cancer cells
  4. progression of entrapped tumor cells through growth factors involved in the wound healing process.

These phenomena may cause a high incidence of surgical treatment failure in patients treated for primary gastrointestinal cancer. The reimplantation of malignant cells into peritonectomized surfaces in a reoperative setting must be expected unless perioperative intraperitoneal chemotherapy is used.

Chemotherapy employed in the perioperative period not only directly destroys tumor cells but also eliminates viable platelets, white blood cells and monocytes from the peritoneal cavity. This diminishes the promotion of tumor growth associated with the wound-healing process. Intraperitoneal chemotherapy should eliminate local recurrence and peritoneal surface recurrence. Removal of the leukocytes and monocytes also decreases the ability of the abdomen to resist an infectious process.

Technique of intraperitoneal chemotherapy

1. Early postoperative technique

After cytoreductive surgery a Tenckhoff catheter is placed through abdominal wall in the approximate area at the highest risk of recurrence. Closed suctions drains are placed in dependent areas in the pelvis and below each diaphragm. The abdomen is closed and then thoroughly lavaged through the Tenckhoff catheter to clear any blood clots or tissue debris. Intraperitoneal chemotherapy administered postoperatively then is drained through the closed suction drains.
Therapy usually occurs in the first three to five postoperative days.

2. intraoperative closed technique

After cytoreduction, inflow and outflow catheters are placed - normally one catheter is placed for inflow of drugs and four as out-flow drainage. After temporary closure of the abdomen, perfusate with chemotherapy is infused. The abdominal wall is manually agitated during the perfusion period in an attempt to promote uniform distribution.
After end of perfusion abdomen is re-opened and the perfusate evacuated.



3. Open abdomen technique (Coliseum)

Catheters are placed in the same way as described above. A silastic sheet is sutured over a Thompson retractor and to the patient´s skin over the abdominal incision. This suspends that abdominal wall creation a ´Coliseum´ container for instillation of peritoneal perfusate. An incision is made in the middle of the sheet to allow manual manipulation of the intra-abdominal contents to prevent stasis of the perfusate.



4. peritoneal cavity expander technique

Peritoneal cavity expander is an acrylic cylinder containing inflow and outflow catheters that are secured over the wound. After cytoreduction is performed in a standard fashion this expander is placed into peritoneal cavity in such a way that small intestine can float freely and manual manipulation is possible. After perfusion is finished the expander will be removed.

Pharmacokinetics

Intraperitoneal (IP) delivery of chemotherapy offers a potential therapeutic advantage over systemic chemotherapy by producing high regional concentrations of drug while simultaneously minimizing systemic toxicities. The selection of agents for perioperative intra-peritoneal chemotherapy is based on the drug's ability to produce a cytotoxic effect over a short time period and pharmacological data.
Mitomycin C, doxorubicin and cisplatin have a slow clearance from the peritoneal cavity. Pharmacokinetic studies of intraoperative intraperitoneal chemotherapy report an absorption of 75- 90% of the mitomycin C and cisplatin within the first hour.
Despite the greatly enhanced drug cytotoxicity because of high concentrations and heat synergy the technique is effective only in treating small volume peritoneal disease.


cytostatic drugmolecular weightAUC ratio
systemic vs. ip.
5-Fluorouracil1301 : 250
Irinotecan 6771 : 18
Oxaliplatin3971 : 25
Cisplatin3001 : 20
Mitomycin3341 : 75
Doxorubicin5441 : 500
Mitoxantron4451 : 640
Paclitaxel8541 : 1000