Influence of mesna on the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients

Mesna, a reactive thiol, often encounters cisplatin and carboplatin in combination protocols involving oxazaphosphorines and platinum drugs. This co-administration might be unfavorable based on the inactivation of platinum drugs by thiol groups in vitro. We investigated whether mesna influences the pharmacokinetics of platinum drugs when co-administered with cisplatin or carboplatin. The pharmacokinetics of platinum drugs were investigated in 18 pediatric patients receiving either cisplatin or carboplatin in a combination with or without mesna. In cisplatin patients, a decrease in the distribution clearance of total platinum was observed when mesna was co-administered (CLd, 2.2 +/- 0.1 mL/min.kg; n = 3), compared to cisplatin without mesna (CLd, 4.8 +/- 1.5 mL/min.kg; n = 5) (p = 0.029, t-test). This might have been caused by an influence of mesna in slowing down the protein binding of cisplatin since a trend (p = 0.057) in prolonged distribution half-life of total platinum was also observed when mesna was present (t(1/2a) 65 +/- 21 min; n = 3) compared to cisplatin without mesna (t(1/2a), 32 +/- 18 min; n = 5). However, the impact of these changes on the area under the concentration time curve (AUC), total clearance (CLt), and volume of distribution (V) for total platinum and ultrafilterable platinum species was hardly noticeable. In carboplatin patients, when mesna was co-administered: AUC (2.5 +/- 0.4 mg.min/mL.400 mg/m2; n = 5) CLt, (6.8 +/- 5.1 mL/min.kg; n = 6), and V (0.7 +/- 0.4 L/kg; n = 6) for ultrafilterable platinum species were not significantly different from when carboplatin were administered without mesna: AUC (2.3 +/- 1.3 mg.min/mL.400 mg/m2; n = 4), CLt (5.8 +/- 4.6 mL/min.kg; n = 5), and V (1.1 +/- 1.1 L/kg; n = 5). Hence, mesna does not significantly influence the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients.     

Application of cisplatin as intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer: analysis of pharmacokinetics and of nephrotoxicity

The purpose of this study was to assess the extent of the systemic absorption of cisplatin during intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer. MATERIALS AND METHODS: The pharmacokinetics and nephrotoxicity of cisplatin were analyzed in patients receiving IHPL (8000 ml of Ringer's solution containing 150 mg/m2 cisplatin and 15 mg/m2 mitomycin C for one hour at 43.5 degrees C). Levels of ultrafiltrable platin were determined by flameless atomic absorption spectrometry. Nephrotoxicity was assessed by nephelometric analyses of urinary marker-proteins. The data were compared to respective analyses in patients receiving intravenous cisplatin. RESULTS: Twenty-four patients received five applications of cisplatin as IHPL (five patients) and 53 applications of intravenous cisplatin (21 patients). Platin levels within the lavage fluid declined monophasically (half-life, 0.48 +/- 10 hours; area under curve (AUC) 29,274 +/- 9075 ng/ml*h). The pharmacokinetic parameters calculated for IHPL vs. intravenous application of cisplatin were: maximum plasma levels 2392 +/- 407 vs. 1349 +/- 692 ng/ml; terminal half-lives 93 +/- 73 vs. 36 +/- 9 hours; AUC 9508 +/- 856 vs. 11,627 +/- 3372 ng/ml*h; total urinary excretion of platinum 24 +/- 6 vs. 49 +/- 13% of dose; renal clearance 127 +/- 34 vs. 145 +/- 35 ml/min. Pathologic urinary albumin excretion occurred on days 9 +/- 0 vs. 5 +/- 2 (maximum 232 +/- 179 vs. 20 +/- 20 mg/l). Plasma creatinine levels rose to 1.5 +/- 0.4 vs. 0.9 +/- 0.1 mg/dl on days 15 +/- 4 vs. 16 +/- 26. The degree of albuminuria was related to the clearance of platin from the lavage fluid (p = 0.048). CONCLUSION: A significant amount of intraperitoneally applied cisplatin is available systemically and probably adds to the nephrotoxicity of IHPL.     

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with an without coadministration of 600 mg degradable starch microspheres (DSM). Mean (+/- standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 +/- 0.69 micrograms/ml) than after DDP alone (2.13 +/- 0.43 micrograms/ml, P less than 0.05), with the area under the curve (AUC0-30 min) values of 15.8 +/- 5.5 and 25.1 +/- 3.8 micrograms x min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 +/- 1.60 micrograms/g) than after DDP alone (0.67 +/- 0.49 micrograms/ml, P less than 0.05). Liver concentrations and tumor-liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole-liver extraction of the drug and a redistribution of blood flow and flow-dependent tissue uptake of platinum.     

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.     

Pharmacokinetics of an etoposide infused over three days: concomitant infusion with cisplatin.

The pharmacokinetics of a 72-hour infusion of 240 mg/m2 etoposide administered concurrently with 90 mg/m2 cisplatin was studied in 12 lung cancer patients. The area under the curve (AUC), elimination half-life, steady state concentration, systemic clearance, renal clearance of etoposide and distribution volume at steady state were 225.4 +/- 39.2 micrograms x h/ml, 8.1 +/- 3.4 h, 3.1 +/- 0.6 micrograms/ml, 18.8 +/- 3.1 ml/min/m2, 3.1 +/- 1.4 ml/min/m2, 9.6 +/- 3.8 l/m2, respectively, which were in accordance with those reported previously in patients treated with etoposide alone. Although concentration at 24 hours, total bilirubin level and total protein level were correlated with the AUC which in turn correlated with hematologic toxicity, the variables were not predictive of hematologic toxicity. We conclude that the concomitant administration of cisplatin at a dose level of 30 mg/m2/day might not affect the pharmacokinetics of prolonged etoposide infusion.     

Regional pharmacokinetic selectivity of intrapleural cisplatin

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m² of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 μg/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m²) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P < 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.     

Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function

cis-Diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin currently undergoing clinical evaluation. Pharmacokinetic studies have been performed in patients receiving CBDCA (20 to 520 mg/sq m) as a 1-hr infusion without hydration or diuresis. Following the end of the infusion, plasma levels of total platinum and ultrafilterable (Mr less than 50,000) platinum (free platinum) decayed biphasically with first-order kinetics (total platinum t alpha 1/2 = 98 min; t beta 1/2 range, 399 to greater than 1440 min; free platinum t alpha 1/2 = 87 min; t beta 1/2 = 354 min). During the first four hr, binding of platinum to plasma protein was limited (24%), with most of the free platinum in the form of unchanged CBDCA (94%). However, by 24 hr, the majority of platinum was protein bound (87%). The major route of elimination was renal, 65% of the platinum administered being excreted in the urine within 24 hr, with 32% of the dose excreted as unchanged CBDCA. No evidence was found from studies on the renal clearance of free platinum to indicate renal tubular secretion (mean free platinum renal clearance, 69 ml/min). However, the plasma clearance of free platinum did correlate positively with glomerular filtration rates (p = 0.005). None of the pharmacokinetic parameters determined were dose dependent. In vitro studies with plasma and urine demonstrated that, in contrast to cisplatin, CBDCA is a stable complex [t 1/2 - 37 degrees; plasma, 30 hr, and urine (range), 20 to 460 hr]. The differences in the pharmacokinetics of cisplatin and CBDCA may explain why the latter complex is not nephrotoxic.     

Pharmacokinetics of carboplatin after intraperitoneal administration

Summary The phamacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i. p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had recived carboplatin (200–500 mg/m²) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24±11. The peritoneal clearance of carboplatin was 8±3 ml/min, which was 12 times less than the plasma clearance (93±32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34%±14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/D_net (D_net=Dose — amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.     

Inhibition of cis-diamminedichloroplatinum secretion by the human kidney with probenecid

The renal handling of cis-diamminedichloroplatinum (CP) was investigated by measuring the renal clearance of creatinine, inulin, and free platinum in ten cancer patients. Free platinum clearances exceeded the glomerular filtration rate in all time periods. For example, at 1 to 2 hr, the mean clearance of free platinum was 224 +/- 32 (S.E.) ml/min compared to a mean creatinine clearance of 94 +/- 15 ml/min or a mean inulin clearance of 94 +/- 17 ml/min (p less than 0.01), indicating secretion of CP or a metabolite. Seven additional cancer patients were treated with probenecid prior to CP. Fractional platinum clearances, calculated as a ratio of free platinum clearance to creatinine clearance, were reduced significantly in the probenecid-treated group (158 +/- 17%) compared to controls (270 +/- 57%) (p less than 0.03). Fractional platinum clearances, calculated as a ratio of free platinum clearance to inulin clearance, were also significantly reduced in the treated group (154 +/- 14%) compared to controls (271 +/- 47%) (p = 0.04). These results suggest that cisplatin is secreted by the human kidney, and this can be inhibited by probenecid. Such maneuvers may be helpful in improving the therapeutic index of this important chemotherapeutic agent.     

Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal of liver function.

The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of lobaplatin in cancer patients. A total of 25 patients with advanced solid tumors not amenable for standard treatment entered the study. Patients had normal organ function or an impaired liver or renal function (two levels). The starting dose of lobaplatin was 50 mg/m2 i.v. given every 3 weeks. The blood and urine of all patients were sampled for the determination of (ultrafilterable) platinum, intact lobaplatin, creatinine, and blood cell counts. No objective responses were recorded. Five patients experienced no change and received 4-10 cycles (median, 6 cycles) of lobaplatin. The extent and duration of hematological toxicity were worse in patients with impaired renal function. Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time curves of ultrafilterable platinum and intact lobaplatin revealed almost identical patterns. The elimination of ultrafilterable platinum [final half-life (t1/2 final) = 131+/-15 min; clearance (Cl) = 125+/-14 ml/min/1.73 m2] was much faster than that of total platinum (t1/2 final = 6.8+/-4.3 days, CI = 34+/-11 ml/min/1.73 m2). No pharmacokinetic differences were observed between patients with normal organ function and those with an impaired liver function within the investigated range. An impaired renal function resulted in an increase of the t1/2 final due to a decrease of the total body Cl that resulted in a higher exposure of the body to the drug. The calculated creatinine Cl was linearly correlated with the total body clearance of ultrafilterable platinum (r = 0.91), which resulted in the dosage formula D = AUCinfinity (1.1 Cl(CrU) + 16), in which D represents dose, AUC represents area concentration-time curve, and Cl(CrU) represents creatinine Cl. The thrombocyte surviving fraction correlated well with the AUC value of ultrafilterable platinum (r = 0.72). It can be concluded that the hematological toxicity and the pharmacokinetics of lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable platinum correlated well with the creatinine Cl and the thrombocyte surviving fraction. In patients with renal function, represented by a creatinine clearance > or =30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is expected to lead to an acceptable extent of thrombocytopenia in a patient with a given renal function. Prospective studies with larger groups of patients are needed to prove the value of this dosage formula.     

Feasibility of intravenous gemcitabine and an intraperitoneal platinum agent in the treatment of ovarian cancer

The goal of this study is to determine the feasibility of intravenous gemcitabine and an intraperitoneal platinum agent in the treatment of patients with ovarian cancer. We performed a retrospective chart review of patients with primary, persistent or recurrent ovarian cancer, who received intravenous gemcitabine and an intraperitoneal platinum agent. Patients received gemcitabine (750 mg/m2) intravenous on days 1 and 8 and cisplatin (100 or 60 mg/m2) intraperitoneal on day 1 every 21 - 28 days. An alternate regimen was composed of gemcitabine (750 mg/m2) intravenous and carboplatin (AUC 5) intraperitoneal on day 1 every 21 days. Dose reductions occurred at the discretion of the prescribing physician.Intravenous gemcitabine and an intraperitoneal platinum agent were administered to 12 patients with advanced primary or recurrent ovarian cancer. Myelosuppression was the most common toxicity. Grade 3 or 4 thrombocytopenia, neutropenia and anemia occurred in 7, 8 and 2 patients respectively. Dose reductions were required in 7 of 12 patients. 10 of 12 patients received 6 cycles of the regimen. Treatment was discontinued prior to 6 cycles in 2 of 12 patients secondary to progression in one case and to grade 4 neutropenia and thrombocytopenia in another.The combination of intravenous gemcitabine and an intraperitoneal platinum agent appears to be a feasible regimen in patients with ovarian cancer. The most common toxicity was myelosuppression, which resulted in dose reductions in almost half of the patients.     

Pharmacokinetics of oxaliplatin in gastrointestinal cancer patients with malignant ascites

The pharmacokinetics of oxaliplatin in plasma and ascitic fluid was investigated in 5 gastrointestinal cancer patients with malignant ascites. Oxaliplatin was administered at 85 mg/m2 by 2-hour infusion in the FOLFOX4 regimen, and the concentrations of total and free platinum were measured. There was a trend of lower plasma C(max) values of total platinum in patients with a larger volume of ascitic fluid. The AUC(0-t) values of mean concentration curves of total plasma platinum, total ascites platinum, free plasma platinum, and free ascites platinum were 31.15, 7.96, 4.93 and 2.93 mg?h/ml, respectively. The concentrations of free ascites platinum were similar to those of free plasma platinum at the last sampling time of 26 h in each patient. The decrease or disappearance of ascitic fluid was observed in 4 patients. These results suggest that oxaliplatin exerted a beneficial effect in gastrointestinal cancer patients with malignant ascites, even when administered intravenously.     

Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Karnofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (CCr) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment CCr. Patients with CCr greater than or equal to 40 ml/min received 400 mg/sq m; patients with CCr 20 to 39 ml/min received 250 mg/sq m; and patients with CCr 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppression, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in CCr due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with CCr. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to CCr, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with CCr of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.     

Pharmacokinetics of cis-diammine (glycolato) platinum (254-S), a new platinum antitumor agent, following an intravenous and intraperitoneal infusion bioactive platinum concentration profile

The pharmacokinetics of cis-diammine (glycolato) platinum (254-S) was investigated in cancer patients following intravenous and intraperitoneal infusion. The serum concentrations of total and unbound 254-S were determined by bioassay and chemical assay as platinum. Platinum detected by bioassay was thought to be active and unchanged 254-S. Almost all of platinum in plasma were found to be active and unbound to protein because of no differences in the concentrations determined by bioassay and chemical assay and in plasma and plasma filtrate. In abdominal ascites, platinum concentrations determined by bioassay corresponded with those determined by chemical assay, suggesting that 254-S was stable in abdominal ascites. The Cmax and AUC of active 254-S in plasma determined by bioassay following an intraperitoneal infusion were about 60% and 60-80% of those following an intravenous infusion, respectively. These results showed that 254-S was well absorbed into systemic circulation from abdominal ascites as an active form. It is concluded that antitumor effect may be obtained following an intraperitoneal infusion of 254-S as well as for the reduction of abdominal ascites.     

Phase I and pharmacological study of an oxaliplatin and carboplatin combination in advanced malignancies.

BACKGROUND: Phase I and pharmacokinetic study to determine the maximal tolerated dose and the recommended dose, as well as the optimal sequence of a carboplatin/oxaliplatin combination delivered every 3 weeks. PATIENTS AND METHODS: Patients received either carboplatin [area under the curve (AUC)-based individually calculated dose (starting dose AUC 4 mg.min/ml), 1 h intravenous (i.v.) infusion] followed by oxaliplatin (110 mg/m(2), 2 h i.v. infusion), every 3 weeks, or the reverse sequence. RESULTS: Sixteen patients were included and only one dose level was assessed. In group A, 10 patients received 23 cycles of carboplatin followed by oxaliplatin. In group B, 6 patients received 20 cycles with the reverse sequence. Delayed recovery from hematological toxicities was treatment-limiting, with mainly moderate thrombocytopenia and neutropenia as dose-limiting toxicities for group A (5 of 10 patients for each) and thrombocytopenia for group B (3 of 6 patients). No febrile neutropenia or grade 3/4 non-hematological toxicity occurred. Pharmacokinetic analysis showed similar mean total platinum AUCs for the two groups: 37.2 +/- 13.7 and 33.6 +/- 9.9 mg.h/l, respectively. One complete response and two partial responses (World Health Organization-International Union Against Cancer criteria, response rate 18.8%) were seen in ovarian, Fallopian and neuroendocrine carcinomas, respectively. CONCLUSIONS: This platinum combination appears feasible and active at the dose of AUC 4 mg.min/ml for carboplatin (Chatelut formula) and oxaliplatin 110 mg/m(2); however, it does not allow a significant increase in platinum dose-intensity delivery.     

腹腔内贝伐珠单抗联合腹腔热灌注化疗治疗卵巢癌腹腔积液的临床观察

目的 观察腹腔内贝伐珠单抗联合腹腔热灌注化疗治疗卵巢癌腹腔积液的疗效和安全性,分析腹水内血管内皮生长因子（VEGF）水平对贝伐珠单抗治疗卵巢癌腹腔积液的临床意义。方法 将46例卵巢癌伴腹腔积液患者随机分为治疗组（n=25）和对照组（n=21）,均应用TC方案（紫杉醇135mg／m2静脉注射d1+卡铂 AUC=5 静脉注射d1）全身化疗,3周重复1次;同时腹腔内给予顺铂40mg／m2+43～45℃ 0.9%生理盐水1500～3000ml热灌注化疗,每2周重复1次,连续治疗6周。治疗组在上述治疗基础上每次热灌注化疗后腹腔内注入贝伐珠单抗300mg,治疗6周。评价患者疗效、生活质量改善及不良反应。酶联免疫吸附法（ELISA）检测46例患者治疗前、后腹水中VEGF水平。结果 治疗组治疗后腹水VEGF水平为（468.30±42.80）pg/ml,明显低于治疗前的（2785.89±305.22）pg/ml（P＜0.05）;治疗组治疗后腹水VEGF水平明显低于对照组治疗后的（820.20±61.49）pg/ml（P＜0.05）。治疗组的有效率（RR）为92.0％（23／25）,对照组为61.9％（13／21）,差异有统计学意义（P＜0.05）。治疗组中VEGF阳性者的RR达1000％,VEGF阴性者为50.0％,差异有统计学意义（P＜0.05）。治疗组的生活质量（QOL）改善率为92.0％,对照组为57.1％,差异有统计学意义（P＜0.05）。46例患者对治疗的耐受良好,无严重不良反应。结论 腹腔内贝伐珠单抗联合腹腔热灌注化疗治疗卵巢癌腹腔积液的疗效优于单纯腹腔热灌注化疗,生活质量明显改善,安全性好,尤其对于腹水VEGF阳性卵巢癌患者更加适合。     

Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

Preliminary phase I clinical study and pharmacokinetics of (1,2-diaminocyclohexane) (isocitrato) platinum (II) or PHIC

PHIC [NSC-350602; (1,2-diaminocyclohexane) (isocitrato) platinum (II)] is a new highly water-soluble platinum derivative. Preclinical studies showed antitumor activity on a wide range of tumors, no cross-resistance with cisplatin and little or no nephrotoxicity in mice and baboons. A phase I clinical trial was then initiated at doses of 300 mg/m2 infused intravenously over one hour without induced diuresis or hydration. Dosages were escalated up to 1500 mg/m2. A total of 29 patients received 52 courses of treatment. The most important side-effect is thrombocytopenia which is rapidly reversible. Nausea and/or vomiting were mild or moderate with onset 1 hr after the end of the infusion and seldom persisted beyond 24 hrs. Measurements of biological parameters did not reveal significant evidence of nephrotoxicity except in one patient who developed urinary tract infection and for whom hemodialysis became necessary. No change in the audiogram could be demonstrated. Peripheral neuropathy was documented in one patient, and in two other patients to whom morphine was given confusional episodes were observed. Although no antitumor effect was observed, there was apparent stabilization of disease. Pharmacokinetic parameters were calculated in twelve out of these 29 patients. Based upon total platinum plasma concentrations, the elimination half-life is 58.3 hrs and the plasma clearance is 21.2 ml/min with an apparent volume of distribution of 7.6 liters. However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min). Mean urinary excretion is 64.4% of the dose after 6 days and 53.1% at 24 hrs. Other administration protocols are suggested, based upon these pharmacokinetic parameters.     

The use of oxaliplatin versus cisplatin in intraperitoneal chemotherapy in cancers restricted to the peritoneal cavity in the rat

Pharmacokinetic studies demonstrated the advantage of intraperitoneal oxaliplatin (1-OHP) for cancers restricted to the peritoneal cavity. The area under the concentration X time curve (AUC) in the peritoneal cavity for both total and ultrafiltered drug was almost 2 times higher for 1-OHP than cisplatin (cDDP). The AUC for ultrafiltered 1-OHP in plasma was also a factor 4 higher than cDDP, indicating that peritoneal tumors received a higher exposure from 1-OHP than cDDP directly in the peritoneal cavity and indirectly via the systemic circulation. Total platinum concentrations in peritoneal tumors of rats were determined after i.p. administration of equimolar doses of 1-OHP and cDDP. In spite of the pharmacological advantages, no significant difference in platinum concentration was demonstrated. In addition, no difference in the distribution of platinum within peritoneal tumors was detected after i.p. treatment with equimolar doses, i.e., platinum concentrations were comparable both in the periphery, 29 +/- 4 ppm for cDDP and 22 +/- 8 for 1-OHP and in the center of the tumor, 18 +/- 3 for both drugs. When CC531 tumor cells were incubated in vitro with equimolar concentrations of 1-DHP and cDDP in vitro, 2 to 4 times less platinum was found in cells treated with 1-OHP, indicating that the uptake of 1-OHP differed from that of cDDP. Oxaliplatin was not cross resistant for cDDP in CC531.RL4 tumor cells, a cDDP resistant cell line, which may indicate its value in ovarian cancer patients who did not respond to earlier cDDP treatment.     

Administration in a hypotonic solution is preferable to dose escalation in intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in rats.

An animal model of intraperitoneal (i.p.) cisplatin chemotherapy using hypotonic solutions of sodium chloride has been developed as a treatment for peritoneal carcinomatosis. The concentrations of platinum in the plasma and in the i.p. fluid of Donryu rats were measured after i.p. injection of hypotonic (103 or 154 mosm/l) and isotonic (308 mosm/l) solutions that contained an equal amount of cisplatin. The maximum concentration (Cmax) and the area under the curve of concentration versus time (AUC) of platinum in the plasma increased proportionately with increases in the dose of cisplatin and they were significantly higher in rats given cisplatin in hypotonic solutions than in those given the drug in isotonic solution. The Cmax and AUC of total platinum were similar for the solution of 103 mosm/l with 2.5 mg/kg cisplatin and the isotonic solution with 5.0 mg/kg cisplatin. The Cmax and AUC of free platinum in the plasma did not increase with increases in the dose of cisplatin in isotonic solution but did increase after hypotonic injection. However, the solutions of lower osmolarity gave a decreased AUC of platinum in the i.p. fluid. Hypotonic conditions continued for 30 min at most after i.p. injection of hypotonic solutions. When the same dose of cisplatin was given to rats with tumors derived from AH100B carcinoma cells, the amount of platinum taken by i.p. solid tumors from the solution of 103 mosm/l was about twice that from the isotonic solution and was much the same as that taken up from the isotonic solution with twice the amount of cisplatin. These results indicate that hypotonic i.p. cisplatin chemotherapy might be preferable to escalation of the dose of i.p. cisplatin in the treatment of peritoneal carcinomatosis.