Pharmacokinetics of intraperitoneal cisplatin and doxorubicin

Intraperitoneal chemotherapy, mainly when performed during HIIC after cytoreductive surgery, is considered potentially curative for the treatment of solid tumors with spread to the peritoneal surface. When selecting antiblastic agents to be administered intraperitoneally, it is important to bear in mind that a low lipophility and a high molecular weight are the ideal drug characteristics. Drugs with these features allow a favorable ratio to be achieved between peritoneal and plasma concentrations, due to the reduced tendency to diffuse through the plasma-peritoneal barrier, even after extensive removal of the peritoneum. Moreover, a low rate of diffusion through the tumor capillaries implies a low rate of drug clearance, with a higher intratumoral drug accumulation. Among the drugs used so far for intraperitoneal chemotherapy, the combination of CDDP and DXR appears to be one of the most effective available regimens with acceptable local-regional toxicity. CDDP has also been extensively employed as a single agent for ovarian and gastrointestinal cancers, under both normal and hyperthermic conditions, while intraperitoneally administered DXR appears to be of greater potential efficacy when associated with CDDP and hyperthermia (41.5 degrees C) following cytoreductive surgery. In our clinical experience with this drug combination, DXR showed a much more advantageous plasma/peritoneal AUC ratio than CDDP (162 +/- 113 and 20 +/- 6, respectively). On the other hand, it has been demonstrated that very high intraperitoneal concentrations of CDDP can be achieved without incurring significant systemic toxicity by using intravenous injection of sodium thiosulphate during HIIC. Penetration of the tumor mass by CDDP is greater than DXR. This phenomenon is enhanced by hyperthermia and by hypotonic solutions of sodium chloride used as the perfusate. Following experimental and clinical results of TNF alpha-based isolated limb perfusion for locally advanced soft tissue sarcoma or melanoma, greater efforts are being made to exploit the potential effect of this cytokine used in association with hyperthermia and other drugs (i.e., CDDP and DXR) suitable for intraperitoneal infusion/perfusion. However, it is not yet clear whether the observed effect of TNF alpha on the peritoneal-plasma barrier, which seems to favor the passage of both drugs into the systemic circulation, is overcome by the positive effect of this agent on drug penetration into tumor. Further pharmacologic studies should be undertaken to clarify whether or not these interactions will be of benefit to the patient. Likewise, liposomes, which in animal models seem to favor tumor uptake of encapsulated DXR, should now be tested in the clinical setting.