Intraperitoneal chemotherapy

Peritoneal metastases have severe complications  that cause  debilitating symptoms and clinical deterioration with a poor prognosis.

Attempts to optimize drug proximity to tumor while minimizing systemic toxicities.

Drug penetration of tumor depends on passive diffusion and extends no more than a few millimeters.

Intraperitoneal administration of chemotherapy is based on the concept of peritoneal dialysis.

The physiologic plasma peritoneum barrier limits uptake of effective concentrations of chemotherapy after systemic administration.

After intraperitoneal administration the peritoneum-plasma barrier prevents systemic drug uptake, facilitating prolonged exposure and higher drug concentrations at the peritoneal surface than in plasma.

This pharmacokinetic advantage produces a local regional therapeutic effect with limited side effects.

The peritoneum it is an extensive serous membrane that covers the abdominal pelvic organs and abdominal wall and functions to include intraperitoneal homeostasis.

Intraperitoneal chemotherapy induces passive concentration driven diffusion from the intraperitoneal fluid into the tissues, interstitial space, and plasma.

Hydrophilic drugs with a high molecular weight and ionized compounds take advantage of the peritoneum+plasma barrier pharmacokinetics.

Drugs use for intraperitoneal administration  should have a large AUC IP:IV ratio.

Technical difficulties include occlusion, infection and rupture of access devices.

There is limited penetration of chemotherapy into peritoneal tumor tissue with the depth of a few millimeters, emphasizing the need for complete resection prior to therapy.

Cisplatin and paclitaxel have high molecular weights and higher rates of clearance from plasma than from peritoneal fluid resulting in peritoneal:plasma concentration ratios of 20:1 for cisplatin and 1,000:1 for paclitaxel.

AUC to plasma in the peritoneal cavity is 12 times higher when cisplatin is infused intraperitoneally then when it is given intravenously and 10-18 times higher when carboplatin is infused intraperitoneally.

Paclitaxel and cisplatinum given in stage III ovarian cancer after optimal debulking results in greater disease free and overall survival compared to patients treated with intravenous chemotherapy alone in a number of clinical trials.

GOG 252 trial failed to show any advantage for IP therapy compared with completely intravenous regimens of carboplatin and plus paclitaxel and suggest there is no longer any role for IP therapy.

Potentially useful agents include mitomycin, oxaliplatin, irinotecan, doxorubicin, and cisplatin.

Hyperthermic intraperitoneal chemotherapy is a single intraoperative procedure that directly delivers chemotherapy in a heated solution to the abdominal cavity after cytoreductive surgery.

The cytotoxic effect of intraperitoneal chemotherapy depends on the concentration and duration of the exposure.

Moderate hypothermia of 41°C to 43°C has potential therapeutic effects when combined with intraperitoneal chemotherapy.

Apart from the direct cytotoxic effects, an induction of programmed cell death, many tumor cells respond to heat by expressing heat shock proteins, which serve as receptors for natural killer cells that in turn elicit an anti-tumor response.

Heat increases tumor cell membrane permeability leading to better drug uptake into malignant cells, a higher intracellular drug concentration, and increased penetration depth of chemotherapy at the peritoneal surface.

Hyperthermia potentiates the cytotoxicity of platinum compounds and alkylating agents by increasing the formation of DNA adducts that lead to cell death.

Heat can impair multiple DNA repair mechanisms that may sensitize cells to DNA damaging agents.

The OVHIPEC trial evaluating effective HIPEC in primary ovarian cancer when it was added to complete surgical resection with patients with stage three primary ovarian cancer with the results suggesting a 3.5 month improvement in recurrence free survival and 11.8 months improvement in overall survival:Patients in this trial were ineligible for primary complete surgical resection due to extensive intraabdominal disease and received neoadjuvant chemotherapy.

Its use in colorectal cancer to prevent to treat peritoneal metastasis is presently under investigation.