Clinical pharmacokinetics of high-dose mitomycin C

Summary The pharmacokinetic profile of high-dose mitomycin C was determined in blood plasma and urine of twelve patients with advanced malignancies in a program including autologous bone marrow transplantation. A total dose of 60 mg/m² was given, either as a single 60-min infusion or divided into infusions of 30 mg/m² on each of 2 days or 15 mg/m² on each of 4 days. One group was given 15-min infusions. Samples of blood plasma and urine were analyzed by high-performance liquid chromatography. Drug concentrations in plasma followed a biphasic pattern, with a terminal elimination half-life of 45 min. This half-life value and other parameters were unaffected by dose level, infusion time, and repeated doses. The lower peak plasma concentrations following 30 mg/m² given as 60-min infusions compared to the same dose given over 15 min may have accounted for a dramatic drop in the incidence of a severe hemorrhagic colitis. Mitomycin C was excreted in urine at about the same rate as it was eliminated from plasma, but a larger percentage of the dose appeared in urine after 15-min infusions than after 60-min infusions. The pharmacokinetic profile, together with clinical observations, suggests that the dose-limiting toxicity of mitomycin C may be related to peak drug levels, and that both these levels and the toxicity are lessened as the infusion time is increased.     

Bladder wall penetration of intravesical mitomycin C in dogs

We examined the kinetics of penetration of mitomycin C (MMC) in the dog bladder wall after intravesical instillation of 20 mg/40 ml, a dose used in patients. Bladder tissues were harvested and concentration-depth profiles were established by analysis of thin tissue slices cut parallel to the urothelial surface of the bladder. Tissue concentrations after a dwell time of 5-7 min were similar to those after 30-120 min. In tissues harvested 60 and 75 min after removal of the dose, MMC was not detected in 5 of 6 samples and was less than 1 micrograms/g at the mucosa in the remaining sample, suggesting a rapid "washout" of the drug. The rapid equilibrium between the drug in urine and bladder tissue indicates that the duration of exposure of the bladder wall tissue was approximately equal to the dwell time of intravesical therapy. Tissue concentrations declined log-linearly with respect to the depth of penetration. The concentration immediately underneath the urothelium (C0) showed considerable intra- and interanimal variability. Bladder distention appeared to increase C0 by several fold. C0 ranged from 2 to 275 micrograms/g wet tissue weight, with a median value of 24 micrograms/g, or 11 micrograms/g when two animals with distended bladders were excluded. MMC concentrations in 3 different sites of the same bladder varied up to 5-fold. Within the capillary-perfused mucosa and muscularis (between 50 and 2000 microns from the urothelial surface), concentrations decreased by 50% for each 500-microns distance. The median concentration at 2000 microns was 1 microgram/g (n = 24). At 2000-3000 microns, tissue concentrations in most (18 of 24) specimens either declined to an asymptotic value or were lower than the detection limit of 0.1 microgram/g. Concentrations in the bladder contents were 200-500 micrograms/ml, the average tissue concentration from 50 to 3000 microns was 10 micrograms/g, and plasma concentrations were less than 0.1 microgram/ml. This supports the therapeutic advantage of intravesical therapy of high local drug concentrations while minimizing systemic exposure. A comparison of the urine concentration and C0 indicated a 30-fold decline in concentration across the urothelium. This suggests the importance of the urothelium as a barrier to MMC absorption. A separate study in our laboratories showed that 16 micrograms/ml of MMC was needed to produce a 90% inhibition of the labeling index of explants of human bladder cancers located in the urothelium (Ta tumor, TNM classification), 25 micrograms/ml in the lamina propria (T1 tumors), and 43 micrograms/ml in the muscle layer (T2 tumors).(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacodynamics of mitomycin C in cultured human bladder tumors

The effects of mitomycin C (MMC) concentration and exposure time on the inhibition of tumor cell labeling index (LI) were studied using surgical bladder tumor samples from 14 patients. The bladder tumors were cultured as 1-mm3 fragments on collagen gels. LI was determined by incorporation of [3H]thymidine and autoradiography. All tumors responded to MMC. However, the sensitivity varied significantly between tumors. At a 2-h exposure, the concentrations required for 50 and 90% inhibition (IC50 and IC90) ranged from 0.237 to 14.9 and 2.76 to 74.5 micrograms/ml, respectively. There was an inverse correlation between MMC activity and tumor LI; the IC values were higher for the more rapidly proliferating tumors. Exposure time had a pronounced effect on MMC activity. Shortening the exposure time from 2 to 0.5 h increased the IC50 3-fold, while prolonging the exposure time from 2 to 24 h decreased the IC50 6-fold. To determine the minimum concentration and exposure time necessary to reduce tumor LI by 90%, the data for 6 tumors were computer fitted to the pharmacodynamic relationship Cn x T = k. The analysis showed that, on average, a 2.5-h exposure of 3 micrograms/ml was needed for 50% inhibition and a 7-h exposure of 8 micrograms/ml was needed for 90% inhibition. A comparison of the IC values of MMC determined in this study with the literature values determined using monolayer and spheroid cultures of established human bladder tumor cell lines showed that the drug activity in cultured tumor fragments ranged from 7- to 5300-fold lower than that in established cell lines. In summary, our data demonstrate a heterogeneity in the response of bladder tumors from individual patients to MMC, a decreased sensitivity to MMC with increasing tumor proliferation, and that drug concentration and exposure time are critical determinants of MMC activity.     

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)     

The stability and antitumor activity of recycled (intravesical) mitomycin C

Although intravesical mitomycin C (MMC) is effective in the treatment of superficial bladder cancer, its expense is a major factor limiting its use. These authors have analyzed the antitumor activity and stability of MMC following 2-hour intravesical instillation in consideration of recycling the drug or using a smaller dose over a longer retention time. The first voided urine samples from 11 patients who received 40 mg MMC intravesically were measured for MMC content by high performance liquid chromatography (HPLC). An average of 50% of the parent drug was recovered. MMC from the urine samples inhibited the growth of a transplantable murine transitional cell carcinoma as effectively as stock drug. Moreover, MMC is relatively stable in human urine at body temperature. These findings suggest that recovery and reuse of the intravesically administered drug is possible and if sterility and appropriate concentrations can be established for the initial and subsequent doses, the drug may be able to be recycled.     

Combination chemotherapy of mitomycin C and cytosine arabinoside in the intravesical treatment for superficial bladder tumors: report 2. Evaluation of prophylactic intravesical infusion therapy

Combined chemotherapy of Mitomycin C (20 mg to 30 mg) and Cytosine Arabinoside (200 mg) was given by intravesical infusion to 25 patients with superficial bladder tumor who underwent transurethral treatment for prevention of postoperative recurrence. The prophylactic effect of this therapy was evaluated as follows. 1) The postoperative recurrence rates by the actuarial method were 4.0% in six months, 8.1% in one year, 22.2% in two years, 37.4% in three years and 37.4% in five years. 2) The prophylactic effect on recurrence tended to be marked on primary tumors, solitary tumors, low grade tumors and relatively large tumors. 3) The correlation of doses and the recurrence rate was significantly observed: prophylactic effect tended to increase in proportion to increase of doses of both Mitomycin C and Cytosine Arabinoside.     

吡柔比星和丝裂霉素C膀胱灌注预防膀胱肿瘤术后复发的临床研究

目的评价吡柔比星(THP)、丝裂霉素C(MMC)40mg、丝裂霉素C 10mg膀胱灌注预防膀胱肿瘤术后复发的疗效和安全性.方法将近期收治的86例膀胱肿瘤术后患者分为3组,分别接受THP、MMC治疗,随访12～20个月.结果THP组26例,复发2例,复发率7.7%;MMC组26例,复发3例,复发率11.5%;MMC组31例,复发11例,复发率35.5%.THP组与MMC组相比差异无显著性(P＞0.05),而THP组和40mg MMC组与MMC组相比则差异有显著性(P＜0.05).结论吡柔比星和丝裂霉素C40 mg 膀胱灌注预防膀胱肿瘤术后复发效果满意,优于丝裂霉素C 10mg膀胱灌注.     

Bladder tissue pharmacokinetics of intravesical taxol

Our previous studies have suggested that the ineffectiveness of intravesical mitomycin C or doxorubicin therapy against muscle-invading bladder cancer is in part because of the inability of these drugs to penetrate the urothelium (the urothelial drug concentration is <5% of the concentration in urine). The goal of the present study was to identify agents that are efficiently absorbed across the urothelium. To evaluate the potential use of taxol in intravesical therapy for bladder cancer, we examined the bladder tissue and systemic plasma pharmacokinetics of intravesical taxol in dogs. Animals (∼8 kg body weight) were given an instillation of taxol at 500 μg in 20 ml water. At 120 min postinstillation, the bladder was emptied and excised, and about 85% of the dose was recovered in the urine. The taxol concentration in the urothelium was about 50% of the concentration in the urine, the concentrations then declined logarithmically in the underlying capillary-perfused tissues. The average tissue concentration (∼2 μg/g) was two to three times the reported plasma concentration of 0.75 μg/ml in patients following intravenous infusion of the >100-fold higher dose of 250 mg/m². The steady-state plasma concentration was <0.02% of the average tissue concentration, and was <0.05% of the maximally tolerated plasma concentration in patients. The octanol:water partitioning coefficients of taxol, doxorubicin, and mitomycin were >99, 0.52, and 0.41, which parallels the rank order of the partitioning across urothelium, i.e. taxol (∼50%) >> doxorubicin ≈ mitomycin C (∼3%). In summary, the partitioning of taxol across the urothelium was more favorable than the partitioning of mitomycin C and doxorubicin, and the systemic concentration of taxol resulting from intravesical treatment was insignificant in spite of the extensive absorption into the bladder. We conclude that intravesical delivery of taxol provides a significant bladder tissue targeting advantage, and that taxol represents a viable candidate drug for intravesical bladder cancer therapy. Received: 20 September 1996 / Accepted: 2 December 1996     

Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial

BACKGROUND: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug's concentration in urine would improve its efficacy. METHODS: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan-Meier analysis with log-rank tests. Statistical tests were two-sided. RESULTS: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P =.005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. CONCLUSIONS: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.     

Prognostic significance of urine cytology on initial follow-up after intravesical mitomycin C for superficial bladder cancer

Seventy patients were given courses of intravesical mitomycin C for residual transitional cell carcinoma of the bladder following partial resection or biopsy. The patients were reassessed 3 months after the initiation of treatment by cystoscopy and cytology from cystoscopic urines and bladder washings. Twelve had no visible cancer at cystoscopic study but had positive urine cytologic findings. The incidence of tumor recurrence, cystectomy, radiotherapy, and deaths due to bladder cancer for this group of cytologically positive partial responders was analyzed. Thirty-three percent (4/12) required cystectomy, none underwent radiation therapy and none died of bladder cancer. These outcomes were compared with that of complete responders (negative cystoscopic and cytologic results) and partial responders with visible tumor (reduction by greater than 50%). We conclude that in high-grade carcinomas, particularly carcinoma in situ, positive urine cytologic findings at the initial 3-month follow-up visit following treatment with intravesical mitomycin C is as ominous a prognostic indicator as endoscopic or biopsy evidence of cancer.     

Enhanced antitumor effect of combination intravesical mitomycin C and bacillus Calmette-Guerin therapy in an orthotopic bladder cancer model

Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is currently the most successful adjuvant agent for the treatment and/or prophylaxis of non-muscle-invasive bladder cancer (NMIBC). However, NMIBCs recur in 60-70% of cases and 30% of these recurrent tumors present with a higher grade and more invasive properties. Patients that do not respond to intravesical BCG therapy are considered to be a challenge for urologists. Thus, novel conservative possibilities should be explored. To test the efficacy of a novel therapeutic approach, we examined the antitumor effect of combination therapy by intravesical administration of mitomycin C (MMC) plus BCG, infusing the two drugs simultaneously, in an orthotopic bladder cancer model. Intravesical BCG and MMC administration showed a dose-dependent survival (n=8 per group). The combination of MMC and BCG provided a significant survival advantage compared to the BCG-alone (p=0.035) and MMC-alone groups (p=0.040) (n=8 per group). The group with combined MMC/BCG exhibited a survival period similar to that achieved with an amount eight times higher that of BCG (n=10 per group). Ki-67 labeling index of cancer cells, showing tumor proliferation, was significantly lower in the combined group compared to the BCG-alone (p<0.05), MMC-alone (p<0.01) and control groups (p<0.01). No difference was detected between the combined group and the BCG-alone group with regard to CD3, T-cell infiltration and CD68 macrophage activity. The combined MMC/BCG treatment decreased the tumor appearance rate, improved the survival period and reduced the cellular proliferation rate in tumors compared to the BCG-alone treatment. The results suggest that the combined intravesical MMC/BCG treatment induced an enhanced antitumor effect against bladder tumors. The combined MMC/BCG treatment also showed a survival period similar to that achieved using a dose eight times higher of BCG-alone.     

Efficacy of intravesical mitomycin C in the treatment of superficial transitional cell carcinoma of the urinary bladder

We treated 47 patients with recurrent transitional cell carcinoma of the bladder with intravesical chemotherapy. Twenty milligrams of mitomycin C per treatment was introduced 7 days after transurethral resection (TUR) or diagnostic cystoscopy, and was repeated at 2-week intervals for five times followed again by cystoscopy. Two more similar courses were administered for a total of 36 weeks. Clinical data revealed no toxicity-related symptoms. Cystoscopic follow-up showed a gradual decline in the presence of tumor to a complete response rate of 87.1% at 36 weeks. Thirteen patients who were previously treatment failures with other drugs responded to mitomycin C.     

Toxicology and pharmacokinetics of intravesical gemcitabine: a preclinical study in dogs.

More active and well-tolerated agents are needed for the treatment of superficial bladder cancer. This study investigated intravesical gemcitabine to establish the toxicology and pharmacokinetics necessary for clinical trials. Beagle dogs (in groups of 2; n = 6) received 100 mg, 350 mg, or 1 g of drug by intravesical administration on alternate days three times/week for 4 weeks. Animals were observed for clinical signs of toxicity; gemcitabine levels and peripheral blood counts were taken three times weekly. The dogs were euthanized, and a full necropsy was performed at days 1 and 14 after the last dose. Intravesical gemcitabine was given at 100 mg (n = 2), 350 mg (equivalent to the 1000 mg/m2 human dose; n = 3), and 3.5 g (n = 1). i.v. gemcitabine was given at 350 mg (n = 2). Plasma samples drawn at time points up to 8 h were analyzed for systemic absorption and clearance of drug. Doses of 100 and 350 mg were well tolerated with no clinical side effects. Necropsies revealed normal bone marrow cellularity and normal bladder histology. At 1 g, signs of severe clinical toxicity were evident, and after only three doses, necropsies demonstrated severe bone marrow hypoplasia, cystitis, and intestinal necrosis. At all intravesical doses, significant systemic absorption was seen. The T1/2 (+/- SD) for intravesical and i.v. administration of 350 mg was 328 (+/-6.8) min and 99.3 (+/-5.2) min, respectively (P<0.001). Intravesical gemcitabine is well tolerated and has no direct bladder toxicity at doses up to 1000 mg/m2. Higher doses result in gastrointestinal, bladder, and bone marrow toxicity.     

Bladder epithelial hyperplasia in F344 rats after intravesical instillation of the antitumor chemotherapeutic agents Adriamycin and mitomycin C

The effects of intravesical instillation of the antineoplastic antibiotics, Adriamycin or mitomycin C, on the urinary bladder epithelium of female F344 rats were evaluated using a combined immunohistochemical and morphological approach. Four weeks treatment with Adriamycin or mitomycin C induced an increase of DNA synthesis and was associated with simple hyperplasia characterized by elevated nuclear cytoplasmic ratios, cytomegaly and pleomorphism. Under the scanning electron microscope (SEM), luminal cell surface alterations such as pleomorphic microvilli were observed. Severity of the lesions was greatest in the Adriamycin group and although treatment of the saline vehicle alone also brought about development of simple hyperplasia, this was very slight and not accompanied by cellular pleomorphism. The present results demonstrated that intravesical instillation of antineoplastic agents can cause a proliferative response and cytotoxicity after only short-term treatment and suggest that this chemotherapy could itself play a possible role in promotion of bladder carcinogenesis or cancer development.     

Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer

Summary Treatment of superficial bladder cancers by intravesical mitomycin C (MMC) chemotherapy gives a varying and incomplete response. Our recent pharmacokinetics and pharmacodynamics studies have shown that treatment effectiveness is limited by drug degradation in acidic urine and by drug dilution due to residual urine volume and urine production. A model was developed to predict drug exposure in tumors in the bladder wall and to correlate drug exposure with antitumor effect. The model is based on the known pharmacokinetic data in patients treated with intravesical chemotherapy, drug-penetration data in the bladder wall of patients undergoing radical cystectomy, and pharmacodynamic data on patient's bladder-tumor chemosensitivity. Computer simulations based on the model were generated. The simulations predicted that changes in treatment parameters would affect the therapeutic outcome in the following rank order: dose>residual volume>urine production>dosing volume>urine pH>dwell time. Tissue exposure could be enhanced by increased dose, complete bladder emptying, reduced fluid intake, use of the minimal dosing volume, and alkalinization of the urine to a neutral pH. Increasing the dwell time from 2 to 4 h gave an insignificant improvement and posed a compliance problem. The selected optimized regimen of a 40-mg dose, no residual volume, 0.62-ml/min urine production, a 20-ml dosing volume, and alkaline urine pH yielded a calculated 8.5-fold increase in tissue exposure over that achieved by the standard regimen, which consisted of a 20-mg dose, 32-ml residual volume, 1.5-ml/min urine production, a 20-ml dosing volume, and acidic urine pH. On the basis of previously established pharmacodynamic data, we hypothesize that the increase in tissue exposure in the optimized treatment would result in a 20% improvement over the standard therapy along with an increase in the recurrence-free rate from 56% to 76% of patients. A phase III efficacy trial comparing the optimized and standard regimens is proposed.Abbreviations MMC mitomycin C - SWOG Southwest Oncology Group - C_u urine concentration - V_u urine volume - V₀ dosing volume - k₀ urine production rate - V_res residual volume - k_a absorption rate constant - k_d degradation rate constant - AUC area under the concentration-time curve; w_1/2 haft-width - Cⁿ x T drug exposure - LI labeling index - T_inst instillation time This work was partly supported by MERIT grant R37 CA-49816 and Research Career Development Award K04 CA-01497 (to J. L.-S. A.) from the National Cancer Institute, DHHS     

Pharmacokinetics of intraperitoneal mitomycin C

The favorable pharmacokinetics of MMC, used during intraperitoneal chemotherapy, has been reported in several studies [11-19]. A major safety issue in studies using intraperitoneal chemotherapy perfusion is the resulting systemic drug exposure. The AUCplasma is determined by the dose, the clearance, and the fraction absorbed from the peritoneal cavity. The reported mean plasma peak concentrations are about one-third of the systemic exposure following a therapeutic dose of MMC given by intravenous administration [30]. The best method to quantify the exposure to MMC are the time concentration profiles (AUC). Because MMC can still be found in plasma the day after intraperitoneal administration, the AUC0-90 is an underestimate of the real AUC; extrapolation to infinity gives the most reliable AUCplasma value. In our series the AUCplasma is about half the AUCplasma when given a therapeutic dose MMC intravenously [30]. What is the best dose in intraperitoneal chemotherapy perfusion? The ideal amount of MMC should include a high AUCperfusate, a high AUCplasma and an acceptable systemic toxicity. In our series grade III/IV leucopenia was observed in 28% patients. We find this rather high percentage acceptable as the problem has proved to be transient, and we have experienced no toxic deaths in recent years. In a phase I study it was estimated that a dose of 25 mg/m2 would result in approximately 10% of grade III/IV leucopenia [20]. Our data indicate that dosing based on body surface area is rational and reliable. The variation between individuals is low. Dosing based on a fixed concentration per liter perfusion fluid is probably more liable to have unforeseen variations, given the fact that we deal with linear pharmacokinetics of MMC [20]. As represented in Fig. 3, the dose of MMC can best be administered in three divided doses, resulting in the more equal exposure of peritoneal structures to MMC during the perfusion. It must be emphasized that our findings only hold true for the perfusion system as used in The Netherlands Cancer Institute. This involves a semi-open abdomen, basic perfusate volume of 3 L, perfusion rate of 1 L/min, abdominal temperature of 40 degrees C, 90 minutes of perfusion, and three drug additions (50% at t = 0, 25% at t = 30 and t = 60 minutes). The differences in perfusion techniques make comparisons of published pharmacokinetics data difficult. Cautions comparison suggest that most groups are dosing far below the maximal tolerated dose. We assume that there is a dose-effect relation for MMC. This means that obtaining a maximal safe dose is important to get maximal results. It seems that better dosing of intraperitoneal MMC can still improve results. The pharmacokinetics of intraperitoneal MMC can, however, be influenced by many details. Open or closed perfusion for instance may make some essential differences. It is therefore important that each treatment group performs its own pharmacokinetics studies on intraperitoneal MMC to achieve the optimal dose method for their chemotherapy perfusion setting. In conclusion, the major advantage of intraperitoneal chemotherapy is the regional dose intensity provided. Following intraperitoneal MMC administration, the affected peritoneal surface is exposed to high concentrations while the systemic toxicity is limited. Comparative analyses on MMC pharmacokinetics are difficult to perform because the diversity of treatment techniques. We recommend administration of MMC, divided in three drug additions, based on BSA.