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Biomedical subjects

E Cvitkovic

Publications and source records attributed to E Cvitkovic.

At least 55 records · Page 3Linked to original sources
PubMed1999

Phase II trial combining mitomycin with 5-fluorouracil, epirubicin, and cisplatin in recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type.

BACKGROUND: This phase-II study was conducted to investigate the potential benefit from the addition of mitomycin to a conventional anthracycline-cisplatin- and 5-fluorouracil-based chemotherapy for recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type (UCNT). PATIENTS AND METHODS: Between July 1989 and December 1991, 44 consecutive patients (M/F 36/8; median age: 45, range 20-72; performance status (PS) 0: 20 patients, PS 1: 14 patients, PS 2: 10 patients) with recurrent or metastatic UCNT were entered in this study after complete clinical, biological, and radiological pre-therapeutic work-ups. Chemotherapy (FMEP regimen) consisted of 800 mg/m2/day 5-fluorouracil in continuous infusion from day 1 to day 4 combined with 70 mg/m2 epirubicin, 10 mg/m2 mitomycin, and 100 mg/m2 cisplatin on day 1, every four weeks for six cycles. Mitomycin was delivered in cycles 1, 3, and 5 only. Eleven patients had isolated loco-regional recurrences, 12 patients had local recurrences associated with distant metastasis, and 21 patients had metastasis only. Toxicity and response were evaluated according to WHO criteria. TOXICITY: Grade 3-4 neutropenia was observed in 122 of 212 evaluable cycles (57%) and 39 of 44 patients (89%); febrile neutropenia occurred in 16 patients (36%) and 24 cycles (11.3%). Grade 3-4 thrombocytopenia was observed in 27 patients (61%) and 45 cycles (21%), including 27 of 45 cycles (60%) with mitomycin. Grade 3 anemia was noted in 18 patients (40%) and 23 cycles (11%), including 18 of 23 cycles (78%) with mitomycin. Grade 3-4 mucositis occurred in 25 cycles (11%) and 14 patients (32%), mainly in those previously treated with radiation therapy in the head and neck area. There were four treatment-related deaths (9%); three of them neutropenia-related, and one of cardiac toxicity. RESPONSE: Forty-four patients were evaluable for response: There were 23 of 44 objective responses (52%), including six complete responses (13%), and 17 partial responses (38%). Additional radiotherapy was given to 13 patients after documentation of response: Nasopharyngeal tumor + cervical nodes (eight patients) and/or on bone metastasis sites (five patients); mediastinal lymph nodes (one patient). At a median follow-up of 87 months (range 71-100), five patients are alive and in continuous complete remission. The median survival time was 14 months and the median time to progression nine months. CONCLUSION: The regimen under study is active in recurrent/metastatic UCNT, but associated with excessive toxicity.

Adult↗
PubMed1999

Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of docetaxel in combination with doxorubicin, and to evaluate the activity in patients with advanced breast cancer. PATIENTS AND METHODS: Forty-two women with untreated metastatic breast cancer (79% with visceral metastases; 52% with prior adjuvant anthracycline therapy) were treated with doxorubicin (40-60 mg/m2) i.v. bolus followed one hour later by docetaxel (50-85 mg/m2) one-hour i.v. infusion every three weeks, without G-CSF support. RESULTS: The MTD occurred at the dose level combining 85 mg/m2 of docetaxel and 50 mg/m2 of doxorubicin, with the DLT being neutropenic sepsis. Neutropenia and/or its complications were manageable and no grade 3-4 or severe non-hematological toxicities were observed. Fluid retention was frequent but never severe. With a median cumulative dose of doxorubicin of 392 mg/m2 (240-559 mg/m2) and a median follow-up time of 29 months (9(+)-41), no congestive heart failure was observed. High activity was observed at all dose levels, particularly the last four, with a response rate of 81% (95% confidence interval (95% CI): 62.5-92.5). Median time to progression was 46 weeks (6(+)-62). Two-year survival was 66%, and median survival has not yet been reached. CONCLUSIONS: Docetaxel-doxorubicin is feasible, safe and highly active. The incidence of febrile neutropenia without G-CSF requires careful monitoring but is acceptable in this setting. There does not appear to be an increase in the cardiac toxicity of doxorubicin. The recommended doses is either docetaxel 75 mg/m2 and doxorubicin 50 mg/m2 or docetaxel 60 mg/m2 and doxorubicin 60 mg/m2, administered every three weeks.

Adult↗
PubMed1999

Decreased topotecan platelet toxicity with successive topotecan treatment cycles in advanced ovarian cancer patients.

The dose-limiting toxicities of the DNA topoisomerase I inhibitor topotecan are hematological. We prospectively analyzed the platelet toxicity pattern in patients receiving topotecan to optimize the clinical management of topotecan hematotoxicity. Twenty-one advanced ovarian cancer patients, all pretreated with cisplatin and paclitaxel, were treated with 1.25 mg/m2/day topotecan as a 30 min infusion for 5 days, every 3 weeks. No prophylactic granulocyte colony stimulating factor (G-CSF) was given. No topotecan dose reduction was planned according to hematologic toxicity. One hundred and thirty-three topotecan courses were administered (median per patient 6; range: 1-15). Despite no dose reduction, the mean platelet nadir values were significantly less pronounced at cycle 2 than at cycle 1 (82 versus 46 x 10(3)/mm3, p=0.0007). Similar differences were found between cycle 1 and any following cycle. The percent of patients experiencing grade 4 thrombocytopenia decreased from 43% at the first cycle, to 15 and 19% at the second and third courses, respectively (p=0.058). We conclude that the currently recommended topotecan schedule is feasible in heavily pretreated ovarian cancer patients without prophylactic G-CSF. The severity of topotecan-induced thrombocytopenia is maximal at the first cycle but significantly decreases from the second cycle in the absence of dose reduction.

Adult↗
PubMed1999

Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics.

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 mg/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one study and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2). At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU-resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Adult↗
PubMed1999

[Phase III trials in oncology].

The randomised trial is the best context for the assessment of any new molecule in oncology. The authors emphasize the methodological aspects of randomised trials and suggest strategies to be adopted in phase III trials, based on the newly orthodox concept of evidence-based medicine, while underscoring the need for context specific adaptations to increase relevance and specificity of sought endpoints, including other means of controlling adequately the clinical experiment without randomization (patient as his own control models). The authors also suggest certain strategic changes. For example, restrictive but relevant eligibility criteria may help decrease the number of patients needed without compromising statistical power as well as other strategies aimed at proving the efficacy of a new molecule without carrying out large trials, which are too long and costly.

Antineoplastic Agents↗
PubMed1999

Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin.

CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane platinum derivative, are cytotoxic agents that have demonstrated clinical antitumor activity in colorectal cancer. Given the therapeutic potential of their combination, we studied the cellular pharmacology of SN-38, the active metabolite of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given alone or in combination. The cytotoxicity analysis by the isobolograms method elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount of detectable ISCs 15 h after a 1-h exposure to 10 microm oxaliplatin was 27% of the ISC peak levels and increased to 68% in the presence of 0.1 microM SN-38. The presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38-induced DNA elongation inhibition, as measured by pulse-labeling alkaline elution. Inhibition of DNA and RNA synthesis was longer after exposure to the combination of oxaliplatin and SN-38 than after exposure to each agent alone. Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra-additive cytotoxicity appears related to major modifications in the cellular response to DNA damage rather than to changes in DNA damage formation. The combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This study provides a rationale for the optimal use of CPT-11 and oxaliplatin in combination.

Adenocarcinoma↗
PubMed1999

Oxaliplatin: a new therapeutic option in colorectal cancer.

Oxaliplatin (Eloxatin; Sanofi, Gentilly, France), a third-generation platinum compound with a 1,2-diaminocyclohexane (DACH) carrier ligand, is a recently developed agent with activity in colorectal cancer (CRC). Preclinical and clinical observations demonstrate synergistic effects with 5-fluorouracil (5-FU), even in 5-FU-resistant tumors. The supradditive pharmacodynamics of the combination have also been proven in previously untreated CRC patients in controlled phase III trials. Due to its excellent safety profile, unique mechanism of action, and lack of cross-resistance with other CRC chemotherapeutic agents, oxaliplatin can be combined with 5-FU, irinotecan (CPT-II), raltitrexed, or other agents. Future directions of development are to determine the optimal administration scheme and the most effective combinations of oxaliplatin with 5-FU or with other anticancer agents. Ongoing controlled studies in adjuvant therapy will further define the place of oxaliplatin in the treatment of CRC.

Animals↗
PubMed1998

Quantitative determination of Ecteinascidin 743 in human plasma by miniaturized high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

A method was developed for the bio-analysis of Ecteinascidin 743 (ET-743) using miniaturized liquid chromatography (LC) coupled to an electrospray ionization sample inlet (TurbolonSpray) and two quadrupole mass analyzers (LC/ESI-MS/MS). Solid-phase extraction was used as a sample pretreatment procedure. Ecteinascidin 743 is a very potent anticancer compound and is administered in microgram m-2 dosages, which demands special requirements in terms of sensitivity for the analytical method supporting clinical pharmacokinetic studies. Using conventional LC/UV, a lower limit of quantitation (LLQ) of 1 ng ml-1 plasma was reached using a 500 microliters sample volume, but LC/ESI-MS/MS permitted an LLQ of 10 pg ml-1. The latter method was found to be accurate and precise, and provided a broad linear concentration range of 0.010-2.50 ng ml-1.

Antineoplastic Agents↗
PubMed1998

Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). ATTIT. Association pour le Traitement des Tumeurs Intra Thoraciques.

The aim of this phase II study was to determine the antitumour activity and safety of trans-1-diaminocyclohexane-platinum (oxaliplatin) in previously untreated advanced non-small cell lung cancer (NSCLC) patients. 33 patients with unresectable and measurable NSCLC were entered into this phase II study between January 1992 and January 1994. Patients had either locoregional disease with performance status 2 (19 patients) or a stage IV disease (14 patients). Oxaliplatin (130 mg/m2) was given on an out-patient basis (2-h infusion, every 21 days) without hydration. Response was assessed after every two courses. One hundred courses were administered, with a mean of three courses per patient (range 1-12). All patients were evaluable for response; 1 had a complete response, and 4 a partial response (overall response rate 15%, 95% confidence interval 5.1-31.9%). The median response duration was 5.9 months. All cycles (n = 100) were evaluable for toxicity assessment. Transient reversible, cold-related finger dysesthesias occurred in 29 patients, but were mild, and disappeared in most cases within a few days. We observed brief episodes of pharyngolaryngeal discomfort (8 patients, 11 episodes) accompanied in 4 cases (3 patients), by transient episodes of inspiratory stridor, leading 2 patients to treatment withdrawal. We conclude that oxaliplatin has activity in poor-prognosis NSCLC and that this treatment is feasible in out-patients; the absence of renal and haematological toxicity makes this drug a good candidate for further evaluation in NSCLC.

Aged↗
PubMed1998

Oxaliplatin: a review of preclinical and clinical studies.

Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand-including oxaliplatin--have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively. Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination. Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.

Animals↗
PubMed1998

Irinotecan-induced immune thrombocytopenia.

BACKGROUND: Irinotecan is currently used as second-line chemotherapy for advanced colorectal cancer. We report a case of severe thrombocytopenia after Irinotecan, suggesting an immune mechanism, in a 53-year-old patient. PATIENTS AND METHODS: The patient's sera were screened for platelet antibodies with an indirect platelet immunofluorescence test (PIIFT). The monoclonal antibody immobilization of platelet antigen assay (MAIPA) was used to characterize the antibody target. RESULTS: We detected an IgG platelet antibody in the patient's serum in the presence of Irinotecan by means of PIIFT, and not in the presence of SN-38, its active metabolite. The specificity of the binding was asserted after CD32 MoAb blockade. The platelet binding site could not be strictly identified with MAIPA and immunoblotting but GpIIb/IIIa can be excluded after experiments with Glanzmann platelets. CONCLUSION: This case can be considered the first documented Irinotecan-induced immune thrombocytopenia.

Adenocarcinoma↗
PubMed1998

Ongoing and unsaid on oxaliplatin: the hope.

Oxaliplatin, the first available diaminocyclohexane platinum, has clinical activity in colorectal and ovarian cancers. Its mechanism of action is thought to be similar to that of cisplatin, its main mechanism being the intrastrand DNA adduct between two adjacent guanins or two adjacent guanine and adenine adducts. Ongoing molecular pharmacological studies of the mechanism of action of cisplatin suggest that platinated adducts are recognized by proteins of the mismatch repair system, including the products of the hMLH1 and hMSH2 genes. DNA mismatch repair defects occur in a wide variety of sporadic human cancers, are the main genetic factor in hereditary non-polyposis colon cancer and a frequent de novo or acquired phenomenon in ovarian cancer and other solid tumours. Moreover, they have recently been reported to be a cause of resistance to cisplatin but not to oxaliplatin, as diaminocyclohexane platinum adducts do not appear to be recognized by the mismatch repair complex. These findings explain the oxaliplatin activity in some cisplatin-resistant tumours. In addition, the good safety profile of oxaliplatin makes it a drug of choice for combination therapy, and it has been shown to be synergistic with other cytotoxic agents, including 5-fluorouracil, cisplatin, carboplatin, topotecan, gemcitabine and CPT-11. The results of several ongoing trials are awaited, but available data demonstrate that oxaliplatin is highly effective in the treatment of advanced colorectal and ovarian cancers. Promising early results suggest that it is also efficacious in non-Hodgkin's lymphoma, breast and non-small-cell lung cancers. As a result of its mechanism of action, its favourable safety profile and the differential profile of its antitumoral activity, the full potential of oxaliplatin as an active, versatile antitumoral agent is yet to be fully explored.

Antineoplastic Agents↗
PubMed1998

Determination of unbound platinum after oxaliplatin administration: comparison of currently available methods and influence of various parameters.

Variations in plasma protein binding may have profound effects on both disposition and activity of drugs, especially for those which are tightly bound to proteins, such as anticancer platinum derivatives. Methods of separation of the non-protein-bound fraction and some technical parameters may influence the results. We have compared ultrafiltration and ultracentrifugation, as well as the effect of potentially interfering factors, upon the determination of the plasma unbound platinum fraction after oxaliplatin administration to cancer patients. Ultrafiltration and ultracentrifugation provided very closely correlated results, so that either technique can be used. The ultrafiltration cut-off (3000-30,000 Da) devices, the type of tube for blood sampling and the type of anticoagulant (none, lithium heparinate or EDTA) did not influence the results markedly. In contrast, results were greatly influenced by freezing: erratic results were obtained on thawed plasmas when compared with those on fresh serum or plasma. Consequences may be important in usual practice, since many pharmacokinetic studies are carried out in multicentric trials with plasma processing centralized in one reference laboratory. The methods for the determination of protein-drug binding should be standardized and guidelines elaborated where optimal conditions for each type of binding assay are given.

Antineoplastic Agents↗