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Flavone acetic acid (FAA, NSC 347512) is a synthetic flavonoid compound with a unique form of preclinical antitumor activity, but its mechanism of action is still not known. In an attempt to exploit the remarkable preclinical activity of this compound in such a way as to allow its use as a clinically useful agent, we performed a phase I and pharmacology study with frequent administration and no hyperhydration or alkalinization. Sixteen patients (9 men, 7 women) were given FAA as 6-h i.v. infusions 2 or 3 times a week (10 and 6 patients, respectively), at doses ranging from 2.5 to 8.1 g/m2. A total of 130 doses were administered during this study. Sedation, arterial hypotension, vomiting and diarrhea were the predominant toxicities observed at the highest dose (8.1 g/m2. One patient developed severe but reversible multiple organ failure. No treatment-related deaths occurred. Pharmacokinetics was linear for the doses studied, with peak plasma levels ranging from 39 to 449 micrograms/ml and a mean terminal half-life of 3.1 h. No drug accumulation was observed with this frequent-administration schedule. No objective response was observed. Three FAA infusions per week at 8.1 g/m2 could be recommended as an optimal and tolerable schedule. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether administration of doxorubicin (DOX) as a continuous infusion or a bolus injection resulted in similar leukemic cell drug concentration in patients with refractory chronic lymphocytic leukemia (CLL). This study was carried out on five patients with refractory CLL, with DOX administered either as a bolus injection (35 mg/m2; CHOP protocol) or as a constant-rate infusion for a period of 96 h (9 mg/m2 per day; VAD protocol). The two types of drug administration were used alternatively with the same patient. Plasma and cellular DOX concentration were determined using high-performance liquid chromatography. Peak plasma DOX levels were higher after the bolus injection than after continuous administration (1509 +/- 80 ng/ml vs 11.6 +/- 1.8 ng/ml, respectively), whereas the plasma area under the curve (AUC) levels were similar. Maximum DOX cellular concentrations were 8629 +/- 2902 ng/10(9) cells (bolus injection) and 2745 +/- 673 ng/10(9) cells (96 h infusion). The cellular AUC after the bolus injection was 2.85 times greater than that observed after continuous administration. This difference was due to a higher cellular peak level followed by a relatively prolonged retention of the drug, with a loss of only 25% in the first 24 h following. These findings demonstrated that in CLL the cellular DOX exposure can be notably modified by the method of drug administration, with higher drug intracellular concentrations being achieved after bolus administration than with the infusion schedule. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy of docetaxel as first-line chemotherapy in patients with unresectable metastatic or locally advanced pancreatic adenocarcinoma and to further characterise the safety and pharmacokinetic profiles of docetaxel. 43 patients were enrolled into this phase II study. Treatment consisted of a 1-h infusion of docetaxel 100 mg/m2 every 3 weeks without premedication with corticosteroids until progression or unacceptable toxicity occurred. Dose modifications were planned for adverse events. Patients were observed for 1 month after the last docetaxel infusion, to document any late adverse events, with a follow-up every 3 months until death. Response rate and duration were the major efficacy endpoints. Response status was reviewed by an external independent panel. Pharmacokinetic analysis was performed during the first treatment cycle. 40 patients were evaluable for response, and all were evaluable for safety. After independent review, partial response was recorded in 6 patients (overall response rate, 15%; 95% confidence limit (CI), 7.7-29.8%) and stable disease was recorded in 15 patients (38%). The median duration of response was 5.1 months (range: 3.1-7.2). The median pain control time was 4.5 months (range: 0-8) and the median time to performance status worsening was 2.3 months (range: 0-4.5). Most patients 40 (93.0%) received a relative dose intensity of more than 70% of the planned dose. The incidence and severity of adverse events reflected the known safety profile for docetaxel. Docetaxel clearance was reduced in patients with elevated concentrations of hepatic enzymes or bilirubin. Docetaxel is an active agent for unresectable metastatic or locally advanced pancreatic adenocarcinoma.

Purpose: The stability of 5-fluorouracil (FU) Roche solutions in a portable infusion pump under prolonged "in-use" conditions (32 degrees C, in the dark) was studied, especially with respect to the formation of the cardiotoxic compounds fluoroacetaldehyde (Facet) and fluoromalonic acid semialdehyde (FMASAld)., Methods: The solutions, prepared according to three protocols frequently used at the Anticancer Centre in Toulouse, were analysed by 19F NMR immediately after preparation (T0) and after 2, 3 or 10 days (TF) in the pump., Results: The commercial solution already contained 64 fluorinated "impurities", among them fluoride ion (F-), FMASAld and Facet. The concentration of FU did not change significantly between T0 and TF, whatever the protocol. The levels of F- had not increased significantly after 2 or 3 days, but had increased by about 50% after 10 days. The increases in FMASAld levels were low (12-28%) albeit significant in the three protocols. The levels of Facet had increased by a factor of about 2 after 2 or 3 days, and by a factor of > 3 after 10 days. The levels of the other fluorinated compounds were constant during the first 2 or 3 days, but had increased by about 30% after 10 days. FU Dakota lyophilizates, analysed immediately after reconstitution, contained neither FMASAld nor Facet. After 2 days at 25 degrees C, low levels of FMASAld were present but Facet could still not be detected., Conclusion: This study showed that special attention must be paid to the risk of increasing concentrations of highly toxic FMASAld and Facet when FU is administered via a pump for long periods of time. It would be preferable not to exceed 3 days of treatment when patients receive FU from a portable infusion pump. This underlines the interest in using a lyophilized formulation of FU in clinical practice.

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m(-2) by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1-9) per patient. The median cumulative dose was 449 mg m(-2). Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1-50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4-52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h(-1) m(-2) and an area under the curve of 6.00 microg ml(-1) h(-1) was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.

Consolidation treatment of advanced ovarian carcinoma, especially the place of intraperitoneal chemotherapy, remains a controversial subject. From January 1988 to July 1995, 39 patients, median age 54 years, received intraperitoneal chemotherapy as consolidation treatment after second-look surgery. At the time of intraperitoneal chemotherapy, 30 patients had no residual disease. Intraperitoneal drug administration used a Tenckoff catheter or a lumbar needle. Treatment combined 5 fluorouracil 1 g/m2 and cisplatin 200 mg/m2, associated with a systemic sodium thiosulfate rescue as nephroprotector. A pharmacological analysis was done for 9 patients: the exposure of peritoneal cavity to cisplatin exceeded that of the plasma by 11 fold. Hematologic and nephrologic toxicity were acceptable. The median follow-up is 43 months. The disease free survival is 36,6 months, but 48,5 months if no residual disease at the time of intraperitoneal chemotherapy. Consolidation treatment by intense intraperitoneal chemotherapy is a feasible approach and might be beneficial in chemosensitive patients devoid of macroscopic remnants, but must be compared with others approaches.

Purpose: The purpose of this study was to determine the bioavailability (F) of etoposide (E;VP-16) after oral administration of the water-soluble prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients., Patients and Methods: Twenty-nine patients received oral EP (capsules, 50 to 150 mg/m2/d of E equivalent) for 5 days in week 1 (course 1), followed every 3 weeks thereafter by a daily intravenous (i.v.) infusion for 5 days of E (80 mg/m2, 1-hour i.v. infusion; course 2); in three patients, the i.v. E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liquid chromatography [HPLC]) were performed on the first day of oral EP administration and on the first day of i.v. E., Results: Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/m2 and in five of seven patients at 150 mg/m2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was observed. The maximum-tolerated dose (MTD) is therefore 150 mg/m2, and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/m2. Twenty-six patients had pharmacokinetic data for both oral EP and i.v. E, whereas three had pharmacokinetic data on the i.v. E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate constant (Ka), 1.7 +/- 1.7 h-1 (mean +/- SD); lag time, 0.3 +/- 0.2 hours; time of maximum concentration (t(max)), 1.6 +/- 0.8 hours; and mean half-lives (t1/2), 1.6 +/- 0.2 (first) and 10.3 +/- 5.8 hours (terminal); the increase in the area under the plasma concentration-versus-time curve (AUC) of E was proportional to the EP dose. After the 1-hour i.v. infusion of E, maximum concentration (C(max)) was 15 +/- 3 micrograms/mL; mean AUC, 88.0 +/- 22.0 micrograms.h/mL; mean total-body clearance (CL), 0.97 +/- 0.24 L/h/m2 (16.2 mL/min/m2); and mean t1/2, 0.9 +/- 0.6 (first) and 8.1 +/- 4.1 hours (terminal). The 24-hour urinary excretion of E after i.v. E was significantly higher (33%) compared with that of oral EP (17%) (P < .001). Significant correlation was observed between the neutropenia at nadir and the AUC of E after oral EP administration (r = .58, P < .01, sigmoid maximum effect [E(max)] model). The mean F of E after oral administration of EP in 26 patients was 68.0 +/- 17.9% (coefficient of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after i.v. E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low ( < or = 100 mg/m2) or high ( > 100 mg/m2) doses., Conclusion: Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/m2/d for 5 days. The recommended oral dose of EP is 125 mg/m2/d for 5 days every 3 weeks in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacologic advantage that could be of potential pharmacodynamic importance for this drug.

Purpose: To evaluate an intensive concomitant chemoradiotherapy protocol of conventional radiotherapy with intermittent cisplatin (CDDP) and continuous-infusion fluorouracil (5-FU) in unresectable, locally advanced squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Fifty-seven patients with unresectable stage IV MO disease (International Union Against Cancer [UICC]/American Joint Committee on Cancer [AJCC], 1987) received radiotherapy 70 Gy followed by CDDP 80 mg/m2 and 5-FU 300 mg/m2/d. Response was assessed 2 months after treatment completion., Results: Thirty patients (52%) received the full treatment schedule; 53 (93%) received full-dose radiotherapy, while 48 (84%) were given at least 75% of the planned chemotherapy doses. Severe mucositis (World Health Organization [WHO]) grade 3 to 4 was the limiting toxicity and was seen in 79% of patients. The median time for mucositis resolution was 8 weeks. Other toxicities were generally manageable, but there were four treatment related deaths (7%). Fifty patients were assessable for activity, with an overall response rate of 70% (95% confidence interval [CI], 58% to 82%). Complete response (CR) and partial response (PR) rates were 42% and 28%, respectively., Conclusion: This simultaneous combined-modality regimen was feasible at the cost of severe mucosal toxicity, which required hospitalization with nutritional, parenteral, and hydroelectrolytic support. The high response rate achieved (70%) did not translate into improved survival, probably due to patient eligibility. The likelihood of cure of this high-tumoral-volume patient population remains low (approximately 10%), despite the association of two therapeutic modalities at full standard therapeutic intensity.

Background: Irinotecan (CPT-11) is a novel water-soluble camptothecin derivative selected for clinical testing based on its good in vitro and in vivo activity in various experimental systems, including pleiotropic drug-resistant tumors. Its mechanism of action appears mediated through topoisomerase I inhibition. The purpose of this study was to describe CPT-11 and active metabolite SN-38 population pharmacokinetics, examine patient characteristics that may influence pharmacokinetics, and to investigate pharmacokinetic-pharmacodynamic relationships that may prove useful in the future clinical management of this drug., Patients and Methods: As part of 3 Phase I studies including 235 patients, pharmacokinetics of CPT-11 and metabolite SN-38 were determined in 107 patients. CPT-11 was administered as a 30-min i.v. infusion according to 3 different schedules: daily for 3 consecutive days every 3 weeks, weekly for 3 weeks, and once every 3 weeks. Patients characteristics were the following: median age 53 years; 62 men, 45 women; 105 caucasians, 2 blacks; performance status was 0-1 in 96 patients; tumor sites were predominantly colon, rectum, head and neck, lung, ovary and breast; with the exception of 6 patients, all had been previously treated with surgery, chemotherapy and/or radiotherapy. CPT-11 and metabolite SN-38 were simultaneously determined by HPLC using fluorescence detection. Pharmacokinetic parameters were determined using model-independent and model-dependent analyses., Results: 168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m2, and a total body clearance of 14.3 L/m2/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m2) and total body clearance (14.8 L/m2/h) yielded almost identical values to the above model-independent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-11 dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUC) increased proportionally and linearly with dosage (Cmax, r = 0.78, p < 0.001); CPT-11 AUC, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001) (ABSTRACT TRUNCATED)

The cardiotoxicity of 5-fluorouracil (FU) was attributed to degradation compounds present in the injected vials, fluoroacetaldehyde (Facet) and fluoromalonaldehydic acid (FMald). These compounds are formed with time in the basic medium necessary to solubilize FU. FU-NaOH vials were much less cardiotoxic than FU-Tris vials on the isolated perfused rabbit heart model since, in FU-Tris vials, Facet and FMald are stored in stable "depot" forms, which are adducts with Tris, whereas, in FU-NaOH vials, they are extensively chemically transformed. Cardiotoxic fluoroacetate (FAC), arising from Facet metabolization, was found in urine of patients, with a ratio FAC/FU catabolites 10-30 fold lower in patients treated with FU-NaOH than in those treated with FU-Tris.

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.

Pharmacokinetics of carboplatin were determined in a patient suffering from advanced ovarian cancer with total hemodialysis-dependent chronic renal failure undergoing 3 consecutive cycles of chemotherapy. Dosage was adjusted to reach active AUC (area under the plasma concentration versus time curve) of ultrafilterable carboplatin. A hemodialysis, performed 24 h after administration results in a decrease of 20% of ultrafilterable carboplatin AUC. The relative dialysis efficacy of ultrafilterable carboplatin was great: 84 +/- 3%. The chemotherapy regimen consisted of carboplatin-cyclophosphamide combination for 6 cycles every 4 weeks. After treatment completion, the patient showed a complete response and remains disease free 16 months after the end of the treatment. Carboplatin-based chemotherapy can be given to patients undergoing chronic hemodialysis without life-threatening toxicity with a dialysis performed 24 h after the administration and with a dose adjustment of carboplatin to reach a AUC of 6 mg/ml.min for untreated patients. In these conditions, response in platinum-sensitive tumors can be obtained.

Retrospective analysis of detailed patient and tumour factors associated with a complete response to combination inductive chemotherapy with CDDP-5FU (96 or 120 hour continuous infusion) was performed using data from 147 patients with a previously untreated squamous cell carcinoma of the oral cavity, oropharynx or pharyngo-larynx following completion of two (29 patients) or three (118 patients) cycles. Adverse reactions to chemotherapy were documented for all 164 patients included in the study. Eight drug-related deaths occurred due to: acute myocardial infarction (five patients), peptic ulcer disease (two patients) and severe neutropenia with sepsis (one patient). Severe non-lethal complications included marrow depletion (14 patients), peptic ulcer (two patients), thrombophlebitis (seven patients), angina pectoris (two patients), stroke (one patient), pulmonary oedema (one patient) and convulsions (one patient). Six patients refused further treatment because of untoward side effects and tumoral progression was observed in three cases. Separate response rates for the primary site and nodes were determined and analysis of respective predictive factors of response was performed. Complete response was obtained in 31 per cent at the primary site versus 18 per cent for the nodes (p < 0.05). The combined (primary site + nodes) overall complete response rate was 22 per cent. Among 11 factors studied (age, sex, performance status, primary site, tumour differentiation, initial resectability, 5FU dosage per cycle, number of cycles, T, N and TN stages), only performance status, N stage, resectability and number of cycles were associated with a combined complete response. Multivariate analysis showed performance status, N stage, TN stage and resectability to be significant predictive factors of a combined complete response.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirteen patients with intra-abdominal malignancies entered a phase I study of fluorouracil (5-FU) given by continuous infusion (96 h) iv and ip, simultaneously, and modulated by high-dose folinic acid-iv. Severe but reversible stomatitis was the only dose-limiting toxicity at a dose of 5-FU of 550 mg/m2/day. Local toxicity (5-FU-induced abdominal pain) was a significant side effect in patients receiving more than 1 cycle. The pharmacokinetic advantage of 5-FU-ip was confirmed in our study (ratio AUC peritoneum/plasma between 160 and 328). The systemic exposure to 5-FU (plasmatic AUC ranging from 73.4 to 173.21 microM) and to AF were found in efficacious ranges. The recommended dose of 5-FU iv and ip is 500 mg/m2/day. This regimen is feasible and may potentially have application for adjuvant chemotherapeutic programs after surgery for colorectal cancer.

Twenty-one patients undergoing either adjuvant or palliative intraperitoneal (ip) chemotherapy had repeated scintigraphic peritoneographies. Significant scintigraphic ip changes were recorded in 11 patients (52%). In patients without residual disease at the time of ip chemotherapy, the rate of ip mal-distribution reached 70%. These alterations did not correlate with clinical complications. Our study suggested that, independently of clinical assessment, scintigraphic peritoneography is a useful test for identifying patients who are no longer suitable for ip treatment, due to inadequate locoregional distribution.

Brequinar (DUP 785, NSC 368390) is a 4-quinoline carboxylic acid derivative with broad spectrum antitumour activity in experimental models that acts as an antimetabolite by specific inhibition of de novo pyrimidine synthesis. We performed a phase I study of brequinar administered as a 10 min intravenous (i.v.) infusion for 5 consecutive days, every 4 weeks. 67 evaluable patients were entered in this study and a total of 130 courses were administered at doses ranging from 2 to 350 mg/m2. The dose-limiting toxicity was myelosuppression with predominant thrombocytopenia. Myelosuppression was dose-related and non-cumulative, with considerable interpatient variability depending on haematological risk factors. The maximum tolerated dose of brequinar was 210 mg/m2/day in poor risk patients whereas patients with good risk haematological profile tolerated higher doses (up to 350 mg/m2/day). Other non-limiting toxicities included nausea and vomiting, mucositis and skin reactions. Brequinar plasma pharmacokinetic profiles were biphasic with alpha half-life ranging from 0.1 to 0.7 h, and beta half-life ranging from 1.5 to 8.2 h. Increase in brequinar area under the plasma concentration versus time curves (AUC) was nonlinear. Day 5 brequinar pharmacokinetics obtained in 21 patients indicated a significant increase in AUC (47%) and half-life beta (133%) compared to day 1 pharmacokinetics in the same patient. Brequinar plasma AUC and the per cent change in platelet count at nadir were correlated (P < 0.001). Although no objective response was observed in this study, one minor response was noted in cervical lymph nodes of a Hodgkin's disease patient.

Purpose: A prospective clinical study was performed to determine the incidence of high-dose continuous intravenous infusion fluorouracil (5FU-CIV) cardiotoxicity., Patients and Methods: Three hundred sixty-seven patients who were given first-cycle high-dose 5FU-CIV were monitored for cardiac function by clinical examination, ECG, and laboratory tests. 5FU-CIV was administered during a 96- or 120-hour period at doses that ranged from 600 to 1,000 mg/m2/d. Associated drugs included cisplatin (56%), mitomycin (12.5%), folinic acid (leucovorin) (7%), and others (14%). Thirty-nine patients (10.5%) received 5FU as a single agent., Results: 5FU-induced cardiac events occurred in 28 patients (7.6%; 95% confidence interval, 4.9% to 10.3%). Nine of them had a history of cardiac disease. Primary tumors included head and neck (n = 13), gastrointestinal (n = 6), breast (n = 3), and others (n = 6). The mean onset time of cardiac symptoms was 3 days (range, 2 to 5). Inaugural symptoms included angina pectoris (n = 18), hypotension (n = 6), hypertension (n = 5), malaise (n = 4), dyspnea (n = 2), arrhythmia (n = 1), or sudden death (n = 1). At 5FU discontinuation, six patients' cardiac symptoms returned to baseline, but 21 patients experienced unstable angina (n = 8), hypotension/cardiovascular collapse (n = 11), pulmonary edema (n = 1), or sudden death (n = 4). The lethality rate was 2.2% (five sudden deaths plus three irreversible collapses). ECG showed repolarization changes (ST segment deviation; T-wave inversion) in 65% and/or diffuse microvoltage in 22% of the patients who presented with cardiac events. Echocardiography showed partial or global hypokinesia in nine of the 16 patients who were examined, and one case of prolonged akinesia. Cardiac enzymes rarely showed an increase (n = 2). In severe but reversible cases, clinical, ECG, and echographic parameters returned to baseline status within 48 hours after the drug discontinuation. A fluorine 19 nuclear magnetic resonance (19F NMR) analysis of urine was performed on 14 patients; six had cardiac symptoms and eight did not. Fluoroacetate (FAC), a known cardiotoxic compound, was detected in all cases., Conclusion: In our study, the incidence of high-dose 5FU-CVI cardiotoxicity was 7.6%. The hypothesis of a toxic cardiomyopathic process requires further confirmation.

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.

[31P] nuclear magnetic resonance spectroscopy was used to analyze body fluids from patients treated with ifosfamide (IF). This technique, which requires no labeled drug, allows a direct study of the biological sample with no need for extraction or derivatization and a simultaneous detection and quantification of all the different phosphorated metabolites in a single analysis. In urine, isophosphoramide mustard was detected in addition to the already known human urinary compounds [i.e., unchanged IF, carboxyifosfamide, 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, ketoifosfamide]. 2,3-Didechloroethylifosfamide itself was not found, but two of its degradation compounds were detected, thus showing a minor route of didechloroethylation of IF in humans. Several other signals corresponding to unknown metabolites or to degradation compounds of IF metabolites were observed. None of them corresponded to IF-activated metabolites (4-hydroxyifosfamide, aldoifosfamide) or to conjugates of IF or its metabolites with mesna. The urinary excretion of IF and metabolites over 24 h amounted to 39 to 50% of the injected dose. Unmetabolized IF was the major compound in 0- to 8-h and 8- to 16-h fractions. 2-Dechloroethylifosfamide and 3-dechloroethylifosfamide were the main metabolites detected in each 8-h fraction. The two unknown compounds at 19.16 ppm and 16.06 ppm represented a non-negligible fraction of the excretion, above that of carboxyifosfamide. Only unchanged IF could be detected in plasma samples. Unmetabolized IF and 3-dechloroethylifosfamide were found in a cerebrospinal fluid sample. Neither IF nor IF metabolites could be observed in the corresponding plasma sample. This indicates a long persistence of these compounds in cerebrospinal fluid.

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.

The phase I trial in oncology follows a very different methodology than in other areas of medicine. Its main objective is the identification of the maximal tolerated dose with short and middle range toxicity limits. In general the therapeutic index of anticancer drugs is narrow and the efficacy of drugs is closely associated with their toxic range: specially hematologic. This toxicity has to be well defined within its nature, its gravity, its dose relationship and its reversibility. It is usually correlated with pharmacokinetic. The cytotoxic agents have as their main target DNA and therefore the long term toxicity is poorly defined and seldom wellknown. The oncology phase I trial is always done in advanced cancer patients and in the great majority of cases after several therapeutic tentative having failed. It is never done in healthy volunteers. Patients have to be informed of the nature of the trial with the possibility of a therapeutic response as an associated objective.

5-Fluorouracil (5FU) cardiotoxicity is thought to be an infrequent toxic effect, usually related to coronary vasospasm. Among 198 patients (pts) receiving 5FU as a continuous infusion (CI) over 96 or 120 h, at a daily dose of 1,000 mg/m2, 13 new cases of 5FU--cardiotoxicity are reported. In all cases but 1, cardiovascular symptoms occurred at the first 5FU-CI course, with mean time of onset of 3 d. Chest pain was the prominent inaugural symptom with angor pectoris (6 pts) and pericarditis (3 pts). Five pts developed cardiogenic shock, which was irreversible in 3 cases. The severity of such an evolution requires prompt 5FU discontinuation, if symptoms occur, and careful hemodynamic supervision during 5FU therapy. One patient experienced typical myocardial infarction, another one epicardo myocardiopathic process with adiastolia. Disorders of repolarisation on electrocardiographic tracing were the prominent abnormalities, associated with a significant increase of QT segment in 3 cases. Re-introduction of 5FU-CI resulted in chest pain recurrence in 2 out of 4 pts, despite calcium antagonist "prevention". In our retrospective study, the incidence of 5FU-CI cardiotoxicity is 6.5%, which is consistent with recent reports (10%). Whether 5FU-induced cardiotoxicity mechanism is related to vasospastic or direct effect remains unclear. However, our series suggests a 5FU-induced post ischaemic myocardial dysfunction as described in the "stunned myocardium" syndrome.

Rabbit very low density lipoproteins (VLDL) have been fractionated by heparin sepharose chromatography into two subpopulations: an unretained fraction (UR) and a retained fraction (R). The separation profiles of VLDL from cyclophosphamide treated rabbits differed from those obtained in normal animals: UR fraction was far more important in treated rabbits than in control animals. Comparative studies of the two VLDL subfractions isolated from treated rabbits have been performed. Polyacrylamide gel electrophoresis in presence of urea showed a similar distribution in both fractions of apolipoproteins X, a group of low molecular weight apolipoproteins detected after antimitotic therapy. SDS - polyacrylamide electrophoresis revealed the presence of one form of apolipoprotein B: apo B100 in the VLDL from treated rabbits giving evidence of their hepatic origin. Relative to the R-fraction, the UR-fraction was characterized by an increased triacylglycerol content and a larger diameter as observed by electron microscopy. In vitro incubations with lipoprotein lipase and reisolation of postlipolysis particles suggest that both VLDL fractions can undergo metabolic conversion to LDL. A decrease of lipoprotein lipase activity after treatment, as previously observed, may thus explain the accumulation of the large VLDL.

In 22 patients cisplatin was infused intraperitoneally in 70 cycles using a dose of 100 and 200 mg/m2. The ratio between peritoneal and plasma AUC was between 10 and 20. No patient showed an objective remission.