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.

Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study.

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.

Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study.

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.

Intensive concomitant chemoradiotherapy in locally advanced unresectable squamous cell carcinoma of the head and neck: a phase II study of radiotherapy with cisplatin and 7-week continuous infusional fluorouracil.

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.

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.

Phase I and pharmacokinetic study of brequinar (DUP 785; NSC 368390) in cancer patients.

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.

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.

Phase II study of pirarubicin (THP) in patients with cervical, endometrial and ovarian cancer: study of the Clinical Screening Group of the European Organization for Research and Treatment of Cancer (EORTC).

From 1986 to 1990, a multicentric phase II study was conducted with pirarubicin, a new semi-synthetic anthracyclin[4'-O-tetrahydropyranyl-adriamycin (THP)]. 87 patients with advanced gynaecological cancers were treated: epidermoid cervical carcinoma (n = 31), adenocarcinoma of the endometrium (n = 28) and ovarian adenocarcinoma (n = 28). THP was administered by short intravenous infusion, for 3 consecutive days, every 3 weeks. The initial dose of THP was 25 mg/m2 day (25% of patients) which was then reduced to 20 mg/m2 day. The average number of courses was 3.7 (range 1-10). The cumulative THP dose was 180 mg/m2 (range 56-594) in cervix and endometrial tumours and 121 mg/m2 (range 58-425) in ovarian tumours. Myelosuppression was the major observed toxicity with grade 3-4 leukopenia and thrombocytopenia in 62 and 19% of the patients, respectively. Severe general complications occurred in 6% of the patients with three fatalities due to infections. Gastro-intestinal side-effects were frequent and usually mild (7% of grade 3 vomiting). 48% of the patients showed alopecia, which was complete in 9 cases (10%). 3 patients experienced cardiac events. No significant antitumoral activity was observed in patients who had failed to respond to previous chemotherapy. Promising antitumoral activity was noticed in untreated cervico-uterine carcinomas with 19% partial responses and 12% complete responses (CR). THP activity was lower in endometrial carcinomas (9.5% CR). Results were found to be negligible in ovarian cancer patients, most of them being refractory to previous chemotherapy containing an anthracyclin compound. On the basis of these results, the definite role of THP in gynaecological cancers deserves to be studied in more favourable programmes (e.g. in combined protocols as first-line chemotherapy).

CPT-11 (irinotecan) in the treatment of colorectal cancer.

Colorectal cancer is one of the most common cancers in the Western World. Although 50% of patients are cured by surgery alone, the outcome is poor in high-risk patients (Dukes stages B2 and C) despite adjuvant chemotherapy with 5-fluorouracil (5-FU)-based regimens. CPT-11 (irinotecan) is a promising new agent for the treatment of colorectal cancer with a unique mechanism of action. CPT-11 is a DNA topoisomerase I inhibitor, which has not demonstrated susceptibility to the P-glycoprotein-mediated multidrug-resistant phenotype. Phase II studies with CPT-11 have demonstrated definite activity against colorectal cancer in both chemotherapy-naive and pretreated patients (response rates of 15-32% observed) even with clinical evidence of resistance to 5-FU. The response rate appears to be consistent, reproducible and equivalent to that achieved with 5-FU plus folinic acid in chemotherapy-naive patients.

A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma.

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.

Stability of commercial solutions of 5-fluorouracil for continuous infusion in an ambulatory pump.

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.

Phase I and pharmacology study of flavone acetic acid administered two or three times weekly without alkalinization.

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.

Determination of the urinary excretion of ifosfamide and its phosphorated metabolites by phosphorus-31 nuclear magnetic resonance spectroscopy.

Phosphorus-31 nuclear magnetic resonance spectroscopy was used to analyze urine samples obtained from patients treated with ifosfamide (IF). This technique allows the individual assay of all phosphorated metabolites of IF in a single analysis without the need for prior extraction. In addition to the classic IF metabolites 2-dechloroethylifosfamide (2DEC1IF), 3-dechloroethylifosfamide (3DEC1IF), carboxyifosfamide (CARBOXYIF), and isophosphoramide mustard (IPM), several signals corresponding to unknown phosphorated compounds were observed. Four of them were identified: one is alcoifosfamide (ALCOIF), two come from the degradation of 2,3-didechloroethylifosfamide (2,3-DEC1IF), and one results from the decomposition of 2DEC1IF. The total cumulative drug excretion as measured over 24 h in nine patients was 51% of the injected IF dose; 18% of the dose was recovered as unchanged IF. The major urinary metabolites were the dechloroethylated compounds, with 3DEC1IF excretion (11% of the injected dose) always being superior to 2DEC1IF elimination (4% of the injected dose). Degradation compounds of 2DEC1IF and 2,3DEC1IF represented 0.4% of the injected dose. The metabolites of the dechloroethylation pathway always predominated over those of the activation pathway (CARBOXYIF, ALCOIF, and IPM, representing 3%, 0.8%, and 0.2% of the injected dose, respectively). In all, 14% of the injected dose was excreted as unknown phosphorated compounds. The interpatient variation in levels of IF metabolites was obvious and involved all of the metabolites. Renal excretion was not complete at 24 h, since 11% of the injected dose was recovered in the 24- to 48-h urine samples.

Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: comparison of bolus administration and continuous infusion.

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.

Specificity of the phase I trial for cytotoxic drugs in oncology.

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.

[Cardiotoxicity of 5-fluorouracil: a question of formulation]. / Cardiotoxicité du 5-fluorouracile: une question de formulation.

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.

Anatomic changes in the abdominal cavity during intraperitoneal chemotherapy: prospective study using scintigraphic peritoneography.

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.

[Cardiotoxicity of continuous intravenous infusion of 5-fluorouracil: clinical study, prevention and physiopathology. Apropos of 13 cases]. / Cardiotoxicité du 5-fluorouracile perfusion intraveineuse continue: étude clinique, prévention, physiopathologie. A propos d'une série de 13 cas.

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.

[Continuous double administration of 5 fluorouracil (intravenous and intraperitoneal) modulated by folinic acid: phase I clinical study and pharmacokinetics in patients with intra-abdominal developing cancers]. / 5-fluorouracile en perfusion continue double voie (intraveineuse et intrapéritonéale) modulé par l'acide folinique: étude clinique de phase I et pharmacocinétique chez des patients porteurs de cancers à évolution intra-abdominale.

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.

[Intraperitoneal high dose chemotherapy as consolidation treatment for advanced ovarian carcinoma: a pilot study]. / Traitement de clôture des adénocarcinomes ovariens de stade avancé: étude pilote de chimiothérapie haute dose par voie intrapéritonéale.

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.