A phase I and pharmacokinetic study of intraperitoneal carboplatin and etoposide

Abstract

Summary Background We attempted to determine the maximum tolerated dose and toxicity of etoposide (VP-16) when administered in combination with carboplatin (CBDCA) (300 mg m-2) and administered via the intraperitoneal (IP) route.Methods and Materials A total of 26 patients were treated on this trial. CBDCA was administered at a fixed dose of 300 mg m-2) while Material and methodsPatient eligibility and characteristics Patients were eligible for participation in this trial if they were 18 years of age or older and had a histologically proven diagnosis of cancer that was refractory to or relapsed after conventional modes of therapy or for which no effective chemotherapy exists. All patients were fully ambulatory and had a life expectancy of at least eight weeks. Patients had to have recovered from the toxic effects of prior therapy and have normal renal (creatinine < 1.5 mg dl-') and hepatic function (bilirubin <1.5 mg%, SGOT less than three times the upper limit of normal). Hematologic parameters required a granulocyte count greater than 1,500 mm-3 and platelet count greater than 100,000 mm-3. Written informed consent was obtained prior to entry on the study. The common toxicity scale was used to grade toxicity.Twenty-six patients were entered. All were evaluable for toxicity. While 21 are evaluable for response on the basis of having either a lesion measurable on physical exam or radiographic study or at subsequent laparotomy. Five patients did not have measurable disease upon entry onto the study. A total of 91 evaluable courses were administered to these patients. Twenty-one patients were female and five were male. The median age was 59 with a range from 26 to 83. ECOG performance status ranged from 0 to 2. Eighteen patients had ovarian cancer, three had gastric, two had colon, and one each had fallopian tube, pancreas and sarcoma. Nineteen patients had received prior chemotherapy, and seven had received prior radiation therapy. Seventeen patients had received prior cisplatin containing regimens, and eight had received prior intraperitoneal chemotherapy. Six patients (two gastric carcinoma, one pancreatic carcinoma,

Pharmacokinetics and toxicity of carboplatin used for hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment of epithelial ovarian cancer

“…The magnitude of the intraperitoneal-to-plasma AUC ratio reflects the rate of carboplatin clearance from the peritoneal cavity relative to the clearance of carboplatin from the systemic circulation. The mean intraperitoneal-toplasma AUC ratio in our study corresponds well to the intraperitoneal-to-plasma AUC ratios reported from phase I studies with intraperitoneal administration of carboplatin, which is described to be in the range of 10-18 [8,[23][24][25]. Several individual physiological parameters can affect clearance from both compartments such as the size of the diffusion area, blood drainage to the peritoneal surfaces, and kidney function, which the broad range of the The peritoneal-plasma barrier prevents direct diffusion of the cytotoxic drug between blood and the peritoneal cavity.…”

Principles and practice of intraperitoneal chemotherapy for ovarian cancer

“…Carboplatin 500 mg/m 2 Thrombocytopenia, leukocytopenia 9 Markman et al (17) 13 Muggia et al (21) 1991 Floxuridine 3000 mg/body/days, for 3 days 2 to 4 log pharmacologic advantage 14 Oza et al (22) 1994 Mitoxiantrone 25 mg/m 2 Leukocytopenia, peritoneal irritation and pain 15 Plaxe et al (23) 1998 Topotecan 4 mg/m 2 Neutropenia 31.2 (AUC) 16 Sabbatini et al (24) 2004 Cisplatin, gemcitabine 75 mg/m 2 (fixed) 759 (AUC) for gemcitabine 17 Speyer et al (25) 1980 5-FU 4.5-5 mM Mucositis, pancytopenia 298 (peak) 18 Zimm et al (26) 1987 Cisplatin, etoposide 200 mg/m 2 (fixed), 350 mg/m 2…”

“…Therefore, IP chemotherapy using platinum agents can be hypothesized as one route of systemic chemotherapy. Table 2 summarizes results of phase I trials with or without pharmacokinetic study (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) . Among those agents, this section will discuss the pharmacology of IP cisplatin, carboplatin, and paclitaxel including animal experiments.…”

“…Table 2 summarizes results of phase I trials with or without pharmacokinetic study (9–26) . Among those agents, this section will discuss the pharmacology of IP cisplatin, carboplatin, and paclitaxel including animal experiments.…”

Historical progress in the initial management of ovarian cancer: Intraperitoneal chemotherapy

“…Pharmacologic studies in the 1970s and 1980s demonstrated favorable profiles of high relative direct drug exposure (high C max and area under the dose response curve [AUC]) for a number of agents subsequently identified to be important for ovarian cancer treatment [10][11][12][13][14][15]. In this regard, both platinum (cisplatin and carboplatin) and taxanes (paclitaxel and docetaxel) have shown superior pharmacokinetic profiles when delivered into the peritoneum directly, compared with intravenous administration [10][11][12]. A sizeable number of phase I and II clinical studies have been performed in the past 35 years to document safety of this strategy and to suggest efficacy.…”