ročník 11,2003 č.4

Hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis

Vitek P., Antos F., Serclova Z., Pala M.

Institute of Radiation Oncology 1st Medical Faculty, Charles University Prague,
Clinic of Surgery, Institute of Postgradual Education in Medicine,
Prague, Czech Republic

The concept of cytoreductive surgery followed by an intraperitoneal heated chemotherapy for peritoneal carcinomatosis has been employed since the end of 80th years. It has resulted in definitive cures in some cases.
The main pitfalls of intraperitoneal chemotherapy were: Increased concentration of the active substance in the peritoneal cavity, delayed absorbance of small ionized molecules, more intensive penetrance of the active substance to tumor tissue under hyperthermic conditions and antineoplastic effect of hyperthermia itself. Cisplatinum and mitomycin C have been predominantly used. A number of phase II studies has proved the feasibility and efficacy of the treatment including the randomised trial proving the superiority of hyperthermic procedure chemotherapy over intraperitoneal chemotherapy alone (1,2).
The methodology of both resection procedure - peritonectomy and hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) keeps continuously evolving. The pharmacology of intraperitoneal administration is rather special and several basic questions for clinical and preclinical trials may be derived.
The selection of the best effective available substance for particular diagnosis. The pharmacokinetics of cytostatics under hyperthermic conditions. The appropriate dosage of particular cytostatics and possibilities of several drugs combination.
We have employed peritonectomy for peritoneal carcinomatosis predominantly in advanced colorectal cancer, ovarian cancer and in several cases of pseudomyxoma peritonei. Therefore the relevant active substances have been employed - mitomycin C, cisplatinum, carboplatinum and 5-fluorouracil. The selection of drugs is based both upon the efficacy proved in particular malignity and adequate pharmacokinetic parameters that maintain the advantage of regional administration like quick plasma clearance and tissue distribution.
The peak concentrations of several drugs after intraperitoneal administration have been well established as well as the "pharmacokinetic advantage" comparing the peritoneal and plasma peak concentrations (3). A high peritoneal concentration and high pharmacokinetic advantage indicate more local effect. However the peak peritoneal concentration is not the only value impacting the antitumor effect of anticancer agents used. There may be more considerable variables finally impacting the concentration of cytostatic drugs in tumor tissue - volume of fluid administered, indwelling time, temperature of heated solution and preceding peritonectomy. As far as the high concentration in tumor is the primary objective of regional therapy, all these variables together should imply the adequate dosage and methodology.
Hyperthermia has been demonstrated to enhance penetration to tumor tissue but also to enhance the absorption of drugs from peritoneum to systemic circulation. Therefore the area under curve (AUC) in peritoneum (peritoneal fluid) may under hyperthermic conditions be even decreased for some agents as has been suggested for carboplatinum (4). This effect is outweighed by a more rapid distribution of the active substance to adjacent tissues including tumor. However it remains questionable, if the increased concentration found in tumor is a result of an increased direct penetration or of a more rapid absorption to circulation and improved enhanced tumor microcirculation. From the clinical point of view the data of increased concentration of cytostatics in tumor may be sufficient regardless of the mechanism, how the agent penetrated into the tumor. The important pharmacokinetic variables implying the dosage of particular agents are: The absorption rate to systemic circulation and the renal excretion rate. This is especially important for cisplatinum. In case of a close perfusion circuit it is the absorption rate what reflects the real systemic dose. The absorption from perfusate rates for currently used cytostatics have been established.

Agent Absorption rate Hyperthermic perfusion time
mitomycin C 70% 2 hrs perfusion (5)
cisplatinum 20%* - 86% 2 hrs perfusion (6,7)
carboplatinum 27% - 77% 90 min. perfusion (8)
oxaliplatinum 50% 40 min. perfusion (9)

Tab. No.1 - Causes of PNF early after liver transplantation
*the absorption rate estimated upon the plasma levels, tissue concentrations not considered

All values indicate a high absorption rate. Major toxicities of particular agents (myelotixicity, nephrotoxicity) depend on a total dose absorbed. Then implication for a dose of drug used for perfusate (dose/perfusate) may result in only slightly increased values compared to a systemic administration. Moreover the absorption rate may be substantially variable resulting in unpredictable systemic exposure as has been proved for carboplatinum (8).
Opposed to this the recent results of HIIC with oxaliplatinum (9) proved a safe increase of the dose/perfusate at least 3 fold maintaining even lower AUC values compared to a current systemic dosage, when the time of perfusion was shortened to 40 minutes. It indicates the dose/perfusate itself is not the only decisive variable.
The indwelling time of perfusate is another important variable determining the efficacy and safety of HIIC. The data on oxaliplatinum absorption indicate a substantial and logical decrease of plasma AUC if the indwelling time is shortened. Unfortunately there is not enough data to establish the relationship between indwelling time and both peritoneal and plasma AUCs quantitatively. In spite of the lack of comparative data the indwelling time should be considered as a variable related to the absorption rate.
The volume of perfusate used for a particular dose of antineoplastic agent is directly related to local concentration in peritoneum. It may impact both penetrance of the agent to tissues and absorption rate. The recent results of oxaliplatinum HIIC have confirmed strong relationship between AUC in peritoneum and rather slight changes of total perfusate volume thus establishing it an important variable. It is recommendable to individualise the perfusate volume according to body surface area.
There are rather controversial references on the impact of peritonectomy on mitomycin C kinetics (5). The peritoneal AUC was influenced significantly by a preceding peritonectomy. Patients, who underwent an extensive peritoneal resection had an increased plasma AUC and decreased peritoneum/plasma AUC ratio. The recent results of the same group proved no relationship between mitomycin C pharmacokinetics and extent of peritonectomy (10). Similar data have been referred for doxorubicin. There are scarce data for platinum derivatives.
We administer hyperthermic intraperitoneal chemotherapy after peritonectomy. The results will be presented in the next paper. The drug regimens consist of 5-FU and mitomycin C for gastrointestinal tumors and of platinum derivatives for ovarian cancer and other tumor types. The dosage is adjusted to body surface area and similar to maximal doses for systemic treatment. The indwelling time of about 2 hrs allows to expect a high absorption to systemic circulation. Such dosage is relevant to previous studies and precludes extensive toxicity in cases of altered kinetics for any reason. New drugs (oxaliplatinum, taxanes) and new combinations of drugs give some space to increase the cytotoxic effect. Kinetics of the active substances may be optimised employing at least 4 integral variables - dose in perfusate, perfusate volume, indwelling time and perfusate temperature.


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