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Biomedical subjects

C Sessa

Publications and source records attributed to C Sessa.

At least 91 records · Page 5Linked to original sources
PubMed1997

Infected aneurysms of the infrarenal abdominal aorta: diagnostic criteria and therapeutic strategy.

From 1976 to 1994 we performed surgical treatment of 18 infected aneurysms of the infrarenal abdominal aorta. The aneurysm had ruptured in nine patients: into the retroperitoneum in six patients, and into an adjacent structure in three patients (duodenum, inferior vena cava, left renal vein). Two patients had an associated spondylitis. Four patients were in shock at the time of surgical treatment. Six patients (including four patients with Salmonella infection and two patients with spondylitis) had positive preoperative blood cultures. Salmonella was the most common microorganism (27%). Anaerobes accounted for 16%. In situ replacement was performed in 13 patients including three procedures performed under emergency conditions with frank purulent infection. Extraanatomic bypass was performed in five patients. Early postoperative death occurred in two patients (11%) due to septic complications (rupture of aortic anastomosis in one patient and rupture of aortic stump in one patient). All surviving patients underwent prolonged antibiotic therapy for at least 6 weeks. Overall mortality secondary to infected aneurysm was 16%. Infection of the aortic graft occurred in four patients (38%) including two patients with Salmonella infection and one patient with spondylitis. One patient developed a false anastomotic aneurysm 6 months postoperatively and was treated by in situ arterial allograft replacement. Postoperative blood cultures were positive in two patients presenting spondylitis and infection of the aortic prosthesis occurred in one of these patients. In addition to rupture, poor prognostic factors included spondylitis and Salmonella infection that were found to greatly enhance the risk of postoperative graft infection following in situ reconstruction.

Aged↗
PubMed1997

Extended phase II study of paclitaxel as a 3-h infusion in patients with ovarian cancer previously treated with plantinum.

An extended phase II study was performed to evaluate single-agent paclitaxel as salvage chemotherapy for ovarian cancer. The aim of this study was to evaluate the 3-h infusion schedule of paclitaxel in terms of toxicity and antitumour efficacy. Furthermore, we analysed the impact on response and survival of the extent of prior chemotherapy and status of resistance against platinum. This study was an open, non-randomised, multicentre trial. The dose of paclitaxel used was 175 mg/m2 in patients who had received one or two prior therapies, and 135 mg/m2 in patients who had received three prior therapies. Paclitaxel was given as a 3-h infusion. Courses were repeated every 3 weeks. 114 patients with platinum-pretreated epithelial ovarian cancer were recruited of whom 112 were found eligible and evaluable for toxicity. 104 patients with bidimensionally measurable disease who received more than one course of chemotherapy were evaluable for response, progression-free (PFS) and survival. Toxicity was generally manageable. Main toxicities were non-cumulative neutropenia with 22.3% of courses with WHO grade 3/4 and peripheral neuropathy which occurred in more than half of the courses and was of WHO grade 2 and 3 in 20.1 and 1.3% of the courses, respectively. Neuropathy was associated with the higher dose per course and with cumulative paclitaxel dose. Objective responses were reported in 20% (21/104) of the patients (95% CI 13-29%) with a median response duration of 36.7 weeks. Survival and PFS for the whole group were 45.9 and 15.1 weeks, respectively. Performance status, number of tumour lesions and extent of prior chemotherapy were found to be prognostic factors for survival. Extent of prior chemotherapy was the only prognostic factor for PFS. Platinum resistance did not predict response to treatment. Paclitaxel 175 mg/m2 given as a 3-h infusion is an appropriate treatment for patients with platinum-resistant ovarian cancer who have not previously received more than two chemotherapy regimens. Paclitaxel did not show results superior to historical data for platinum retreatment in patients with platinum-sensitive, recurrent ovarian cancer.

Adult↗
PubMed1997

Treatment of childhood Hodgkin's disease with COPP or COPP-ABV (hybrid) without radiotherapy in Nicaragua.

BACKGROUND: Childhood Hodgkin's disease (HD) in low-income countries has been reported to have distinct presenting features, including a high prevalence of the mixed cellularity subtype, which also seems to be associated with poorer prognosis. Further investigations are needed to evaluate these issues. Another controversial aspect of childhood HD is the use of radiotherapy (RT) in its treatment and the growing concern about its serious adverse side effects. In this paper, data on the diagnosis and outcome of children treated without RT in a low-income country (Nicaragua) are reported. PATIENTS AND METHODS: Forty-eight consecutive children aged 0-15 years, diagnosed at 'La Mascota' Hospital of Managua (Nicaragua) from January 1990 to October 1995. entered this study. Follow-up was updated in May 1996. Clinical and histopathological staging was performed according to Ann Arbor and Rye criteria, respectively. Treatment consisted of COPP (six cycles) for stages I or IIA, or COPP-ABV hybrid): eight cycles for stages IIB or III, and ID cycles for stage IV. Total cumulative doses of adriamycin and bleomycin in this protocol are, respectively, 200 and 80 mg:sqm for stages II B or III and 250 and 100 mg/sqm for stage IV. RESULTS: The median age of the 48 patients at diagnosis was seven years, and the mean age was 7.9 years (range 3-15 years). Clinical stages were IA in 5, IIA in 9, IIB in 6, IIIA in 5, IIIB in 14, and IVB in 9. Histopathologically, 25 cases presented with mixed cellularity, 15 with nodular sclerosis, 5 with lymphocytic predominance and 3 with lymphocytic depletion. Four patients did not proceed with treatment and were lost to follow-up. Two patients (stages IIIB and IVB), who never achieved complete remission (CR) during treatment, presented progressive disease at the end of the scheduled chemotherapy. The remaining 42 patients were in complete remission at the end of chemotherapy. Following discontinuation of therapy, one patient (stage IA) was lost to follow-up and two patients with stage IIIB, who were in CR after the second chemotherapy cycle, relapsed 20 and 9 months following the diagnosis. EFS at three years is 100% for the 25 patients with stages I, II, IIIA and 74.9% for the 23 patients with stages IIIB or IV. CONCLUSION: The presenting features found in these patients are similar to those reported from other low-income countries. In our experience, however, the high prevalence of the mixed cellularity subtype was not associated with poorer prognosis. Satisfactory results have been achieved in patients with stages I, II or IIIA HD using COPP or COPP-ABV (hybrid) regimens without RT. The treatment was also well tolerated and can thus be recommended for these patients in low-income countries, where RT facilities may be scarce or unavailable. The use of more aggressive treatment schedules and/or RT on involved fields in front-line treatment may, however, be needed for the more advanced stages IIIB or IV. Large studies with adequate follow-up are needed to evaluate whether, if RT is omitted, higher cumulative doses of more toxic drugs are required and thus compare the long-term toxic effects of different treatment modalities.

Adolescent↗
PubMed1997

Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer.

BACKGROUND: The toxicity profile of prolonged infusions of paclitaxel in combination with cyclophosphamide in metastatic breast cancer has already been defined. The objective of this dose-finding study was to determine the maximum tolerable doses (MTDs) of shorter (three-hour) infusions of paclitaxel in combination with i.v. bolus cyclophosphamide in patients who had previously received a maximum of one chemotherapy for advanced breast carcinoma. The MTD of the same regimen with granulocyte colony-stimulating factor (G-CSF) support was then established. PATIENTS AND METHODS: Eighty women with metastatic breast cancer received a total of 352 fully evaluable courses of therapy. The starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2 given every three weeks. At least three patients were treated at each dose level and if there were dose-limiting toxic effects during the first cycles three additional patients were entered. G-CSF support (5 micrograms/kg s.c.) was added to the second cycle if specific dose-limiting toxicities had occurred during the first cycle. The MTD was defined as the dose level at which more than two of six patients presented dose-limiting toxicities during the first cycle. RESULT: Febrile neutropenia (n = 4) and severe thrombocytopenia (n = 1) defined the MTDs of paclitaxel as 200 mg/ m2 and of cyclophosphamide as 2,000 mg/m2 with or without G-CSF in patients with and, respectively, without prior chemotherapy for advanced disease. Non-hematologic toxicity was moderate. Recommended doses were 200 mg/m2 of paclitaxel and 1,750 mg/m2 of cyclophosphamide with or without G-CSF in patients with and, respectively, without prior chemotherapy. The overall response rate was 25% and 50%, respectively, in patients with and without prior chemotherapy for metastatic disease. Complete remissions (9%) were reported only in patients without prior chemotherapy; antitumour activity in women with anthracycline-resistant disease, with an 8% response rate (95% CI: 1%-26%), was poor. CONCLUSIONS: Paclitaxel at 200 mg/m2 and cyclophosphamide at 1,750 mg/m2 can be safely administered every three weeks to women with advanced breast cancer. The moderate antitumour activity observed with the schedule tested argues against its use as initial therapy for advanced breast cancer.

Adult↗
PubMed1997

Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine adenocarcinoma.

PURPOSE: To evaluate the toxic effects and antitumour activity of a multidrug regimen with cisplatin, epirubicin and paclitaxel (CEP) as initial therapy in patients with uterine adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients with histologically-confirmed diagnoses of locally advanced, recurrent or metastatic cervical or endometrial adenocarcinoma entered the study. Treatment consisted of epirubicin (E) given at 70 mg/m2 followed by paclitaxel (P) (175 mg/m2 over three hours) and cisplatin (C) (50 mg/m2), repeated every three weeks. Eligibility criteria also included age < or = 75 years, no previous chemotherapy, no previous radiotherapy to the tumour parameters, bidimensionally-measurable lesions, no previous or ongoing cardiac disease, and renal and liver function within normal limits. Complete blood cell counts were repeated weekly, and tumor response was assessed every three cycles. A maximum of eight courses was administered in responding patients. RESULTS: From January 1996 to January 1997, 30 patients with endometrial adenocarcinoma and 19 with cervical adenocarcinoma entered the study, for a total of 213 cycles of treatment. In patients with endometrial carcinoma the overall clinical and pathological response rates were 73% (95% CI, range 54%-88%) and 35% (95% CI, range 16%-57%) respectively; in patients with locally advanced cervical carcinoma the overall clinical and pathological response rates were 64% and 62%. WHO grade 3-4 neutropenia occurred in 61% of the patients, with one possible toxic death. Retreatment had to be delayed for at least one week because of persisting neutropenia in 34% of the patients. Mild peripheral neuropathy and stomatitis were observed in 46% and 23% of the patients. One patient presented acute congestive heart failure after the third cycle of treatment. CONCLUSION: The high antitumour activity and the good tolerability of CEP suggest that this regimen should be prospectively compared to standard combinations as initial treatment of advanced endometrial carcinoma.

Adenocarcinoma↗
PubMed1997

Estimation of the haematological toxicity of minor groove alkylators using tests on human cord blood cells.

We evaluated the myelotoxicity and the anti-tumor potential of tallimustine, three of its analogues and carzelesin, with melphalan as reference substance. Tallimustine was tested by clonogenic assays on both human bone marrow (BM) and cord blood (hCB) cells, the other compounds on hCB only. The degree of inhibition of the haemopoietic progenitors GM-CFC, CFC-E and BFU-E was evaluated after exposure to different concentrations. The same schedules were tested on five tumour cell lines. We found that the dose-response curves for tallimustine on BM and hCB cells were similar. Carzelesin was shown to be the most potent of the substances tested and to be the one with the best in vitro therapeutic index; of the distamycin analogues, the one bearing an alpha-bromoacrylic group (FCE 25450) had the best index. For melphalan, tallimustine and carzelesin, the concentration inhibiting the growth of 70% of progenitor cells in vitro (ID70) was similar to the concentrations found in the serum of patients treated at the maximum tolerated dose (MTD). We conclude that hCB cells may be used instead of BM cells for in vitro myelotoxicity tests. Therapeutic indexes can be extrapolated from this model and could help in selecting the most promising analogue for further clinical development. The in vitro-active concentrations are similar to myelotoxic concentrations in patients, suggesting a predictive value for the assay.

Adult↗
PubMed1997

DNA minor groove binding ligands: a new class of anticancer agents.

This paper gives an overview of the available pharmacological and clinical data of a new class of anticancer drugs which act by binding DNA in the minor groove, comprising cyclopropylpyrrolo-indole (CC-1065) derivatives and Distamycin derivatives. The emphasis of this review is placed on the distinctive mode of action of these drugs. Molecular pharmacology studies indicate that CC-1065 and its derivatives, and the benzoyl mustard derivative of Distamycin, Tallimustine, possess the most striking DNA sequence specificity of alkylation observed to date for an alkylating agent of relatively small molecular weight. The effects on the regulation of gene transcription, the perturbation of the cell cycle, and the mechanism involved in the repair of the DNA lesions induced by these drugs all strongly support the view that minor groove ligands act by a mechanism different from those previously described for other anticancer drugs. The CC-1065 derivatives, Adozelesin and its prodrug, Carzelesin, and Tallimustine were found to be very effective against several murine tumours and human xenografts, and were shown to be active against experimental tumours that were resistant to other antineoplastic agents, including conventional alkylating agents. The clinical studies performed so far do not confirm in humans the remarkable antitumour activity observed in mice. The major reason appears to be a very high susceptibility of human bone marrow to both CC-1065 derivatives and Tallimustine as compared to mouse bone marrow, which makes it impossible to administer these drugs at sufficiently high doses to exert antitumour effects. The search for new minor groove binders, which possess a different DNA sequence specificity of alkylation and which are less cytotoxic for human bone marrow cells, is still in progress. It will be several years before it is possible to draw firm conclusions on the clinical effectiveness of this class of drugs.

Journal Article↗
PubMed1997

Paclitaxel (175 mg/m2 over 3 hours) with cisplatin or carboplatin in previously untreated ovarian cancer: an interim analysis.

The side effects of cisplatin (75 mg/m2) in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (175 mg/m2 over 3 hours) are expected to be more severe and frequent than those of carboplatin (area under the concentration-time curve of 5) in combination with the same dose of paclitaxel, but the combinations are expected to be equally effective. A disadvantage of the cisplatin-based regimen is that patients need to be admitted to the hospital. The carboplatin regimen can be administered to outpatients. We tested both combinations administered every 3 weeks in a randomized phase III study in patients with previously untreated epithelial ovarian cancer. An interim analysis for toxicity was performed in 145 patients shortly after study closure. We observed a difference in the incidence of nausea, vomiting, and neurotoxicity favoring the women treated with the carboplatin regimen, but this regimen caused more myelotoxicity. Maturation of the study is awaited before survival data can be analyzed and final conclusions can be drawn.

Adult↗
PubMed1997

Dose-finding study of paclitaxel and cyclophosphamide in women with advanced breast cancer.

The primary aim of this study was to define the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion and cyclophosphamide given by intravenous bolus every 3 weeks in patients with breast cancer. Patients had received a maximum of one prior chemotherapy for advanced disease. The maximum tolerated dose of the combination was also determined with granulocyte colony-stimulating factor (G-CSF) support. The 80 women who took part in this study received 347 fully evaluable courses of therapy. Starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2; G-CSF support (5 microg/kg subcutaneously) was added at the subsequent cycle if specific dose-limiting toxicities had occurred during the previous cycle. Febrile neutropenia and severe thrombocytopenia defined the maximum tolerated doses as paclitaxel 200 mg/m2 and cyclophosphamide 2,000 mg/m2, with or without G-CSF support, in patients with or without a prior chemotherapy. Recommended doses were paclitaxel 200 mg/m2 and cyclophosphamide 1,750 mg/m2 in these two groups of patients. The overall response rate was 25% among patients who had received prior therapy for metastatic disease and 50% in patients who had not been previously treated. Complete remissions were reported in 9% of patients, but only among those who were previously untreated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

[Carotid revascularizations by venous grafting: long-term results].

Carotid artery reconstruction (CAR) may be achieved through a variety of techniques. The method of choice is based upon the patient's symptoms, the diffusion of the atheromatous lesion in the internal carotid artery and the experience of the surgical team that usually deals with these patients. Between January 1987 and May 1995, we performed 185 CAR using saphenous vein graft. The indication for surgery was atherosclerotic occlusive desease in all patients, sixty-two per cent of whom were asymptomatic. In the early postoperative period one patient died of aspiration, two patients suffered a stroke (one major and one minor) and five patients had a transcient ischemic attack due to carotid clamping intolerance. Two late restenosis and two graft occlusions occurred. The cumulative operative morbidity and mortality rate was 1.6%. This series demonstrates than venous grafting for carotid reconstruction yields satisfactory short- and long-term results and is a valuable alternative to endarteriectomy. Follow-up by Duplex-scan revealed no evidence of morphological degradation of the vein grafts.

Adult↗
PubMed1996

The last 3 months of life of cancer patients: medical aspects and role of home-care services in southern Switzerland.

The clinical data on terminal cancer patients who have died since the establishment of a program of collaboration between community services and the cancer center of Canton of Ticino, southern Switzerland, were retrospectively analyzed to describe the characteristics of patients seen and the effect on them of a home-care program coordinated by the cancer center. The home-care program is based on five geographically grouped community-based domiciliary services, with the addition of one nurse responsible for coordination and one physician from the oncology center. Selection criteria for participation in the home-care program are defined. The main outcome measures were: number of hospitalizations and median hospital stay during the last 3 months of life; reasons for and median length of last hospitalization; place of death of patients who had home care and those who did not. In the group of 993 patients analyzed, the median contact time with the cancer center was 9.5 months (10th percentile: 1 month, 90th percentile: 71 months); the most frequent neoplasm was lung cancer (22%) with the briefest contact time (7.5 months; 10th percentile: 1 month; 90th percentile: 21 months); 13.5% of patients were never hospitalized; half of the patients had a total hospital stay of 24 days or longer and 23% died at home. The sociodemographic and medical characteristics of home-care users were similar to those of the home-care non-users and to those of the overall group. In the group of home-care users (32% of the total) 22% were never hospitalized, half of the patients had a total hospital stay of 17 days or longer, and 43.5% of them died at home. These values were significantly different (P > 0.001) from those reported in the group of home-care non-users. Palliative care, provided at home through community-based domiciliary services, is associated with less frequent and shorter hospitalizations in the last 3 months of life. Medical oncology and palliative treatments should be mutually complementary to improve patients care. Cancer centers should be involved in the planning and coordination of supportive-care domiciliary services.

Aged↗
PubMed1996

Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative.

NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m2 on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m2 was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m2. NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m2 after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10-15% of the dose after administration by both routes, whereas that of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m2 for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated or have undergone previous chemotherapy only once.

Administration, Oral↗
PubMed1996

Treatment of ovarian cancer with surgery, short-course chemotherapy and whole abdominal radiation.

BACKGROUND: The primary aim was to induce a high number of pCR in early (FIGO IC, IIB + C) - and advanced (FIGO III-IV) - stage ovarian cancer with a surgery plus 4 cycles of cisplatin and melphalan (PAMP) regimen. The second objective was to prevent relapse with WAR in patients in remission after chemotherapy. PATIENTS AND METHODS: 218 eligible patients were treated after staging laparotomy with cisplatin 80 mg/sqm i.v. on day 1 and melphalan 12 mg/sqm i.v. on day 2 q 4 weeks. Response was verified by second-look laparotomy. WAR was carried out with the open field technique on a linear accelerator (daily dose: 1.3 Gy, total dose: 29.9 Gy) in patients with pathological or clinical CR or pathological PR with microscopical residual disease. RESULTS: 146/218 patients (67%, 95% CI: 61%-73%) responded to PAMP: 56 (26%) achieved pCR, 24 (11%), cCR, 56 (26%) pPR and 10 (5%) cPR (c = clinical, p = pathological). Multivariate analyses revealed that in advanced stages (92 cases in remission), the achievement of pCR was the most important factor for longer time to failure (TTF) and survival. Only 51/118 (43%) patients in remission received WAR. Early-stage patients <= 55 years were more likely to have WAR than patients older than 55 years (77% vs. 23%; p = 0.02). Advanced-stage patients with cCR were less likely to be irradiated than patients with pCR or pPR (10% vs. 51%; p = 0.003). Toxicity of PAMP was acceptable with 10% of WHO grade 4 hematologic toxicity. Acute hematological toxicity of WAR caused interruption (33%) or incompleteness (33%) of irradiation in the majority of patients. CONCLUSIONS: PAMP is an effective treatment for advanced ovarian cancer with a 67% response rate after 4 cycles. For the majority of patients in remission, WAR as a consolidation treatment was hardly feasible. For these patients new treatment modalities to consolidate remission are needed.

Adult↗
PubMed1996

Paclitaxel induces significant changes in epidoxorubicin distribution in mice.

BACKGROUND: Inhibition of Pgp can affect the distribution and the pharmacokinetics of anthracyclines, causing marked changes in their toxicity. Since both paclitaxel and cremophor are substrates of Pgp, it was hypothesized that they could modify the pharmacokinetics of anthracyclines in a similar fashion. PURPOSE OF THE STUDY: To evaluate whether pretreatment of mice with cremophor or paclitaxel dissolved in cremophor could induce changes in the distribution of epidoxorubicin (EpiDx). MATERIALS AND METHODS: Male CDF1 mice were treated with ethanol or cremophor or paclitaxel and 30 min later with EpiDx (15 mg/kg i.v.). EpiDx serum and tissue levels were determined at several time points after EpiDx treatment by high pressure liquid chromotagraphy (HPLC) assay coupled with fluorimetric detection. RESULTS: Pretreatment with paclitaxel dissolved in cremophor induced a highly significant increase in EpiDx levels in all tissues examined including heart. At 8 h heart levels in mice treated with EpiDx alone, EpiDx and cremophor and EpiDx and paclitaxel were 8.3 micrograms/g, 10.9 micrograms/g and 16.7 micrograms/g (P < 0.01), respectively. Cremophor alone induced a similar increase in spleen EpiDx levels but had only a moderate effect on heart and lung EpiDx levels. Levels of doxorubicin (Dx) aglycone in kidney and liver of mice treated with paclitaxel and EpiDx were higher than those in mice treated with EpiDx alone. CONCLUSIONS: A pharmacokinetic interaction between paclitaxel and EpiDx was clearly demonstrated in mice. The much higher tissue levels of EpiDx after paclitaxel pretreatment may be the reason for the increased toxicity of EpiDx when administered soon after paclitaxel.

Animals↗
PubMed1996

Phase I clinical and pharmacokinetic study of carzelesin (U-80244) given daily for five consecutive days.

Carzelesin (U-80244), one of the synthetic DNA minor groove binding cyclopropylpyrroloindole analogues, was selected for clinical development because of its high potency, promising antitumor activity in murine solid tumors and leukemia, and significant therapeutic efficacy against colon and rhabdomyosarcoma xenografts. In this Phase I study, carzelesin was given daily for 5 consecutive days to (a) determine the maximum tolerable dose (MTD) and the pattern of toxicity of this schedule; (b) define the pharmacokinetic profile of the parent, as was done for the intermediate compound U-76073 and the DNA-reactive agent U-76074; and (c) document any antitumor activity observed. Carzelesin was given as a 10-min infusion with a constant-rate infusion pump. Treatment was repeated every 4 weeks or when blood counts had recovered to normal values. The starting dose of 12 microgram/m2/day was escalated by 20-30% increments until the MTD (defined as the dose leading to grade 4 hematological or grade 3 nonhematological toxicity in at least two of six patients) was reached. Pharmacokinetic studies were planned on days 1 and 5 of the first cycle in at least two patients per dose level. Plasma levels of carzelesin, U-76073, and U-76074 were determined by high-performance liquid chromatography with UV detection and a detection limit of 0.5 ng/ml. Twenty-five patients were entered in the study, and 56 cycles were evaluable for hematological toxicity. Subsequent dose levels evaluated were 24, 30, 35, and 40 microgram/m2. Both neutropenia and thrombocytopenia were dose limiting and cumulative, with a high interpatient variability. Neutropenia occurred earlier (median time to neutrophil nadir and recovery, 15 and 29 days, respectively) than thrombocytopenia (median time to platelet nadir and recovery, 25 and >/=26 days, respectively); there were delays of treatment because of persisting thrombocytopenia in all patients treated at the MTD. At the MTD, the peak plasma concentrations of carzelesin were achieved at the end of the infusion and were higher than those found cytotoxic in vitro against tumor cell lines. Carzelesin was detectable up to a maximum of 1 h after the infusion. Smaller amounts of U-76073 were detectable for a maximum of 30 min only at the MTD, whereas U-76074 was never found. An 8-month partial remission was reported in one previously untreated patient with hepatocellular carcinoma at 40 microgram/m2. The MTD was fixed at 40 microgram/m2 daily; 35 and 30 microgram/m2 are the daily doses recommended for Phase II studies in good- and poor-risk patients. The daily regimen for 5 days seems to offer no advantage over the single intermittent schedule that has been selected for the Phase II program in Europe.

Adult↗