A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802).

BACKGROUND: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. PATIENTS AND METHODS: A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m(2), 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m(2) bolus, 600 mg/m(2) 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m(2) 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). RESULTS: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. CONCLUSION: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction.

BACKGROUND: We aimed to establish the superiority (or noninferiority if superiority was not achieved) in terms of time to progression (TTP) of irinotecan/5-fluorouracil (IF) over cisplatin/5-fluorouracil (CF) in chemonaive patients with adenocarcinoma of the stomach/esophagogastric junction. PATIENTS AND METHODS: Patients received either IF: i.v. irinotecan 80 mg/m(2) 30 min, folinic acid 500 mg/m(2) 2 h, 5-fluorouracil (5-FU) 2000 mg/m(2) 22 h, for 6/7 weeks or CF: cisplatin 100 mg/m(2) 1-3 h, with 5-FU 1000 mg/m(2)/day 24 h, days 1-5, every 4 weeks. RESULTS: In all, 333 patients were randomized and treated (IF 170, CF 163). Patient characteristics were balanced except more IF patients had Karnofsky performance status 100%. TTP for IF was 5.0 months [95% confidence interval (CI) 3.8-5.8] and 4.2 months (95% CI 3.7-5.5) for CF (P = 0.088). Overall survival (OS) was 9.0 versus 8.7 months, response rate 31.8% versus 25.8%, time to treatment failure (TTF) 4.0 versus 3.4 months for IF and CF, respectively. The difference in TTF was statistically significant (P = 0.018). IF was better in terms of toxic deaths (0.6% versus 3%), discontinuation for toxicity (10.0% versus 21.5%), severe neutropenia, thrombocytopenia and stomatitis, but not diarrhea. CONCLUSION: IF did not yield a significant TTP or OS superiority over CF, and the results of noninferiority of IF were borderline. However, IF may provide a viable, platinum-free front-line treatment alternative for metastatic gastric cancer.

A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients.

BACKGROUND: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. PATIENTS AND METHODS: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle). RESULTS: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m(2) twice daily, oxaliplatin 130 mg/m(2)) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m(2) twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). CONCLUSION: The MTD for this combination in MCRC is capecitabine 825 mg/m(2) twice daily days 1-14, oxaliplatin 130 mg/m(2) day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.

Prediction of carboplatin clearance from standard morphological and biological patient characteristics.

BACKGROUND: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. PURPOSE: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. METHODS: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles). RESULTS: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. CONCLUSION: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients.

Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m2 (30-90 min i.v. infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and appeared to be dose related, reversible and noncumulative. However, interpatient variability of toxic effects was substantial. Prolongation of the infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and anemia. CPT-11 plasma disposition was bi- or triphasic with a terminal half-life of 9.3 h. CPT-11 area under the plasma concentration versus time curves increased linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the plasma concentration versus time curve correlated significantly with that of CPT-11, but not with that of CPT-11 dose. Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m2. Using this weekly schedule, recommended doses for phase II studies are 100 mg/m2 in high risk patients and 115 mg/m2 in others.

Plasma and cellular pharmacokinetics of mitoxantrone in high-dose chemotherapeutic regimen for refractory lymphomas.

We have studied the plasma and peripheral leukocyte pharmacokinetics of mitoxantrone associated, in a high-dose regimen, with cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation. Nineteen patients with refractory lymphoma were involved in a clinical trial with escalated doses (15-90 mg/m2) of mitoxantrone administered by 30-min i.v. infusion 8 days before an autologous bone marrow transfusion. Mitoxantrone was measured by high-performance liquid chromatography in plasma and peripheral lymphocytes. The plasma pharmacokinetics of mitoxantrone was linear between 15 and 90 mg/m2: total body clearance (19.3 +/- 6.2 liter/h/m2) and volume of distribution at steady state (486 +/- 254 liter/m2) were not altered by increasing the dose. The exposure of bone marrow transplant to the plasma residual concentration of mitoxantrone was correlated with the limiting hematological toxicity of the regimen (P < 0.001). At all times, the mitoxantrone concentration in peripheral cells was much higher than in plasma and was retained at a constantly high concentration level. Whereas cellular versus plasma maximum concentration ratio was near 1, the area under the concentration +/- time curve ratio reached 100, suggesting a long elimination half-life from cells. Plasma and cellular pharmacokinetics data of mitoxantrone reinforce the idea that this drug is a good candidate for high-dose chemotherapy regimen.

Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer.

PURPOSE: A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships. PATIENTS AND METHODS: Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection. RESULTS: The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome. CONCLUSION: Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.

High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study.

PURPOSE: To assess, on a multicenter basis, the feasibility of treating advanced cancer patients with high-dose irinotecan. PATIENTS AND METHODS: Thirty-five patients who met the usual phase I criteria (26 men and nine women) were included. Primary tumor sites were colon, head and neck, unknown primary, kidney, liver, and others. All had been previously treated. Irinotecan was given at the maximum-tolerated dose (MTD) (600 mg/m2) or the level below (500 mg/m2) as a 30-minute infusion once every 3 weeks. RESULTS: Eighteen patients were entered in the four participating centers at the MTD of 600 mg/m2. This dose level was clearly shown not to be feasible: 14 patients (78%) had grade 3 to 4 neutropenia, with febrile episodes in 11 patients; grade 3 to 4 diarrhea was observed in nine patients; and one toxic death occurred. Subsequently, 17 not heavily pretreated patients were included at 500 mg/m2 and carefully monitored. The safety of this dose level was considered acceptable: 41% of patients had grade 3 to 4 neutropenia, 24% experienced grade 3 to 4 diarrhea, and no febrile granulocytopenia or toxic death occurred. Six partial responses were documented in metastatic colorectal cancer, all in patients who had previously received conventional chemotherapy, four in patients who had exhibited progressive disease under fluorouracil (5FU)-based chemotherapy. CONCLUSION: We plan to study the higher dose-intensity 500-mg/m2 level on good-risk and carefully monitored patients. This could enlarge the spectrum of tumors sensitive to irinotecan and improve the already good results observed in colorectal cancers.

Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second-look laparotomy.

PURPOSE: The purpose of this study was to evaluate the efficacy and tolerance of recombinant human interferon gamma (rIFN-gamma) as second-line treatment in patients with persistent disease at second-look laparotomy. PATIENTS AND METHODS: One hundred eight patients with residual disease at second-look laparotomy were treated with rIFN-gamma (20 x 10(6) IU/m2) administered intraperitoneally (IP) twice a week for 3 to 4 months. In the absence of clinically assessable disease, response to rIFN-gamma was assessed with a third-look laparotomy. RESULTS: Of 98 assessable patients, 31 (32%) achieved a surgically documented response, including 23 patients (23%) with a complete response (CR). The age and size of residual tumor were significant prognostic factors for the response to rIFN-gamma. A 41% CR rate was observed in 41 patients younger than 60 years and with residual tumor less than 2 cm. The probability of response was independent of previous response to first-line chemotherapy. The median duration of response was 20 months and the 3-year survival rate in responders was 62%. Response to rIFN-gamma was the most significant prognostic factor for survival of patients with residual disease. Adverse events included fever, flu-like syndrome, neutropenia, and liver enzyme disturbances. No significant peritoneal fibrosis was noted. CONCLUSION: These results support the potential interest of IP rIFN-gamma as adjuvant treatment in ovarian cancer. Controlled prospective trials are required to determine its place in the therapeutic strategy of this malignancy.

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.

PURPOSE: To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS: Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS: Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION: CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study.

PURPOSE: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. RESULTS: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine. CONCLUSION: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.

Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: pharmacokinetic and pharmacodynamic evaluation.

Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: human ovarian carcinoma OVCAR-3 implanted i.p. Nude mice were treated i.p. with a total dose of topotecan of 12.5 mg/kg delivered in 1, 5, 10, 20, 40, or 80 daily injections. The toxicity was maximal when the total dose was delivered within 5 and 10 days of treatment. However, the efficacy was the greatest (all of the mice cured) in the 20-day schedule using 0.625 mg/kg/day, hence, making this latter schedule the most efficient without any major toxicity. A pharmacokinetic study was conducted to identify parameters related to the efficacy and toxicity of topotecan in our model. The use of a population pharmacokinetic approach allowed us to define a therapeutic window: maintaining plasma concentrations above 0.2 microM for >10 h was necessary for an optimal antitumor effect and avoiding plasma concentrations >0.7 microM allowed a manageable toxicity. Finally, Topo I activity was monitored in ascites from animals treated with different topotecan administration schedules. The optimal schedule defined above allowed for sustained inhibition of Topo I activity associated with a greater antitumor activity. These in vivo data constitute a rationale for clinical studies testing this type of administration.

Estrogen and progestin regulation of the progesterone receptor concentration in human endometrium.

The concentration of the progesterone receptor (PR), both cytosol and nuclear, has been measured in the endometrium of 31 normal menstruating women during the 2 phases of their menstrual cycle and compared with the plasma 17 beta-estradiol and progesterone concentrations. There was no relationship between PR concentrations and the plasma steroid levels when the 2 phases of the cycle were considered; however, a statistically significant correlation (r = 0.70; P less than 0.005) was observed between PR concentration and plasma 17 beta-estradiol when only the follicular phase was considered. PR was then measured in the endometrium of 14 postmenopausal patients treated with ethinylestradiol at increasing doses with or without association of chlormadinone acetate. Ethinylestradiol was shown to increase PR concentration (P less than 0.05), and chlormadinone acetate was found to prevent this increase. These data suggest that in humans, as in other mammalian species, the endometrial PR concentration is under estrogen and progestin control.

PIP: The respective roles of estrogens and progestins on endometrial progesterone receptors (PRs) were evaluated in 16 proliferative-phase and 15 secretory-phase biopsy samples from normally menstruating women. Plasma estradiol-17-beta and progesterone were measured in both cytosol and nuclear extracts. In addition PRs were measured in biopsied tissue taken from 14 postmenopausal women who had been treated with increasing doses of ethinylestradiol (with or without chlormadinone acetate) who presented with breast cancer. Among the normally menstruating women, there were no relationships between PR concentrations and plasma steroid levels when both phases of the cycle were considered; however, a correlation of significance (P .005) was apparent between PR concentration and plasma 17-beta-estradiol when only the follicular stage was considered. In the postmenopausal women who were under treatment, ethinylestradiol administration seemed to increase PR concentration (P ,05), whereas concomitant treatment with chlorimadinone acetate blocked this increase. Therefore, mammals seem to have endometrial PR levels controlled by both estrogens and progestins.

Human pharmacokinetics of N-L-leucyl-doxorubicin, a new anthracycline derivative, and its correlation with clinical toxicities.

A pharmacokinetic study of N-L-leucyl-doxorubicin, a new derivative of doxorubicin, has been undertaken during a phase I trial in 19 patients with advanced cancer after intravenous bolus administration at doses ranging from 30 to 240 mg/m2. The pharmacokinetics of N-L-leucyl-doxorubicin was linear with a total body clearance of 41.3 +/- 25.7 L/hr/m2. N-L-leucyl-doxorubicin was extensively metabolized into doxorubicin, which appeared in plasma immediately after N-L-leucyl-doxorubicin infusion. The mean molar doxorubicin/N-L-leucyl-doxorubicin area under the curve (AUC) ratio was 0.49 +/- 0.22 and was independent of the administered dose. A relationship has been established between the doxorubicin AUC (r = 0.74; p less than 0.001) and the surviving factor in white blood cell counts. Other toxic side effects (thrombocytopenia or stomatitis) did not correlate with any pharmacokinetic parameter. These findings suggest that the degree of metabolization of N-L-leucyl-doxorubicin into doxorubicin may be responsible for the toxicity, that is, N-L-leucyl-doxorubicin may simply represent a pro-drug for doxorubicin.

Dose and time dependencies of 5-fluorouracil pharmacokinetics.

OBJECTIVES: The purpose of this study was to examine the interpatient and intrapatient variability of the Michaelis-Menten plasma parameters of 5-fluorouracil administered according to a schedule combining a bolus of 400 mg/m2 followed by 22-hour infusion of 600 mg/m2 for 2 consecutive days. PATIENTS: A pharmacokinetic population approach was used to analyze the data from 21 patients with colorectal cancer. RESULTS: The 5-fluorouracil plasma concentrations versus time were best described by a two-compartment model with nonlinear elimination from the central compartment. The relationships between the pharmacokinetic parameters and patient characteristics were tested. On day 1 the mean values (with interindividual variability as expressed by the coefficient of variation) were 1390 mg x h(-1) (20%), and 5.57 mg x L(-1) (22%) for the maximum rate of elimination, and the half-saturating plasma concentration. The maximum rate of elimination was positively correlated to the body surface area and the percentage of liver involvement by metastatic disease determined by tomodensitometric examination. The model was successfully tested with independent data sets corresponding to other schedules. The analysis of this intrapatient variability showed that the half-saturating plasma concentration increased from day 1 to day 2, especially in the patients with low lymphocyte cell dihydropyrimidine dehydrogenase activity. CONCLUSION: The pharmacokinetic parameters obtained in this study would be useful to predict the 5-fluorouracil plasma concentrations following other schedules of administration of 5-fluorouracil and to study the possible pharmacokinetic interactions between 5-fluorouracil and other drugs.

Early assessment of a new anticancer drug analogue--are the historical comparisons obsolete? The French experience with pirarubicin.

Data of all phase II studies of pirarubicin (THP-doxorubicin) have been analysed for toxicity or activity in breast cancer and compared with published reports on doxorubicin, epirubicin or mitoxantrone used as single drugs. A graph of the 95% confidence intervals for each event was used. The results suggest that pirarubicin is as effective as other intercalating drugs in breast cancer and grossly better tolerated than doxorubicin, especially alopecia and cumulative cardiotoxicity. The equimyelotoxic doses of each drug were also estimated. The methodology and the validity of such historical comparisons is discussed: they cannot replace prospective randomised phase III studies, and do not allow definitive conclusions. However, most comparative trials of anticancer drug analogues cannot answer the right questions because their objectives are not adequate (especially for equiefficacy). But early evaluation by historical comparisons can help the conception of phase III studies.

Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines.

Oxaliplatin (L-OHP) is a new platinum analogue that has shown antitumour activity against colon cancer both in vitro and in vivo and is now used in the chemotherapeutic treatment of metastatic colon and rectal cancer. L-OHP like cisplatin (CDDP), is detoxified by glutathione (GSH)-related enzymes and forms platinum (Pt)-DNA adducts lesions that are repaired by the nucleotide excision repair system (NER). We investigated the cytotoxicity and the pharmacology of L-OHP and CDDP on a panel of six colon cell lines in vitro. We showed that GSH and glutathione S-transferase (GST) activity were not correlated to oxaliplatin cytotoxicity. Pt-DNA adducts formation and repair were correlated with CDDP, but not with L-OHP cytotoxicity. The determination of ERCC1 and XPA expression, two enzymes of the NER pathway, by reverse transcriptase-polymerase chain reaction (RT-PCR), demonstrated that ERCC1 expression was predictive of L-OHP sensitivity (r(2)=0.67, P=0.02) and XPA level after oxaliplatin exposure was also correlated to L-OHP IC(50) (r(2)=0.5; P=0.04). The knowledge of such correlations could help predict the sensitivity of patients with colon cancer to L-OHP.

Modulation of cisplatin cytotoxicity by human recombinant interferon-gamma in human ovarian cancer cell lines.

Cytotoxic interactions between recombinant human interferon-gamma (IFN gamma) and cisplatin have been studied in six ovarian cell lines (IGROV1, NIHOVCAR3, SKOV3, OVCCR1, 2008 and its cisplatin resident variant 2008/C13*). Studies were performed using a cell survival assay. Results were assessed using median effect analysis. Synergy between these two drugs was observed in cell lines sensitive to IFN gamma, whatever their relative sensitivity or resistance to cisplatin, suggesting that IFN gamma enhances the cytotoxic activity of cisplatin. This interaction is not due to an increase in platinum accumulation in cells. This combination of drugs should be evaluated against human ovarian cancer xenografts in nude mice before its use in clinical practice.

Phase I/II pharmacokinetic study of mitoxantrone by continuous venous infusion in patients with solid tumours and lymphoproliferative diseases.

Phase I and pharmacokinetic studies were performed in order to evaluate the maximum tolerated dose and the efficiency of 120 h continuous venous infusion (CVI) of mitoxantrone. 25 patients suffering from either metastatic solid tumour or refractory lymphoproliferative disease were included in the study. The starting dose was 2 mg/m2 per day and was increased by a 0.2 mg/m2 per day step dose. The main toxicity observed was leukopenia which became limiting in more than 50% of the patients receiving 2.4 mg/m2 per day (12 mg/m2 over a 120 h period); this dose was defined as the maximal tolerated dose in these pretreated patients. One partial response and three stable diseases were observed. A plasma plateau concentration of mitoxantrone (2.13 [S.D. 0.54] micrograms/1 at 2 mg/m2 per day, 2.56 [1.32] micrograms/1 at 2.2 per day and 3.46 [1.32] micrograms/l at 2.4 mg/m2 per day) was reached within 24-48 h. It was linearly related to the administered dose. The mean plasma clearance of mitoxantrone was 27.8 [14.2] l/h/m2 and the volume of distribution of the beta phase averaged 2327 [2125] l/m2. An inverse relationship was established between the mitoxantrone clearance and the degree of hematologic toxicity. This 120 h CVI mitoxantrone schedule was safe and could be repeated every 3 weeks in an outpatient setting. The relationship between mitoxantrone clearance and the drug related haematotoxicity could be used for an individual dose adjustment.