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D Mavroudis

Publications and source records attributed to D Mavroudis.

At least 55 records · Page 3Linked to original sources
PubMed2001

A dose-finding study of the weekly administration of paclitaxel in patients with advanced solid tumors.

The purpose of this study was to determine the dose-limiting toxicities and the maximum-tolerated dose (MTD) of weekly administration of paclitaxel in patients with advanced solid tumors. Twenty-six patients with advanced solid tumors were treated with escalated doses of paclitaxel (starting dose 70 mg/m(2)/wk with increments of 10 mg/m(2)/wk) for 4 consecutive weeks every 6 weeks. No intrapatient escalation or growth factor support was allowed. The DLT was exceeded at the dose of 120 mg/m(2)/wk, and the dose-limiting events were grade IV neutropenia and treatment delay because of incomplete hematologic recovery. There was no cumulative myelosuppression. Grade IV neutropenia occurred in four (6%) cycles, and there was one episode of febrile neutropenia. Grade II/III fatigue occurred in 19 (73%) patients, resulting in discontinuation of treatment in 2 of them; grade II neurosensory toxicity and grade II alopecia occurred in 8 (31%) patients each. The MTD, which is also the recommended dose for further phase II studies, was 110 mg/m(2)/wk. Among the 21 patients with bidimensionally measurable disease, 2 (10%) partial responses were observed, both in patients with heavily pretreated advanced breast cancer. The weekly administration of paclitaxel for 4 consecutive weeks in cycles of 6 weeks is a feasible, safe, and active outpatient regimen that merits further evaluation in combination with other anticancer agents.

Aged↗
PubMed2001

A dose-finding study of irinotecan (CPT-11) plus a four-day continuous 5-fluorouracil infusion in advanced colorectal cancer.

OBJECTIVE: Irinotecan (CPT-11) has shown considerable activity in colorectal cancer, and its combination with 5-fluorouracil (5-FU) represents an attractive approach. A phase I study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of CPT-11 in combination with a continuous infusion of 5-FU for 4 days. METHODS: Forty-two patients with histologically confirmed metastatic colorectal cancer who had not received prior treatment for advanced disease were enrolled. The patients' median age was 64 years; 26 (62%) patients were men, and the performance status (WHO) was 0 in 26 (62%) patients, 1 in 15 (36%) and 2 in 1 (2%). Twenty-two (52%) patients had 2 or more metastatic sites. CPT-11 (starting dose 200 mg/m(2)) was administered as a 30-min intravenous infusion with increments of 50 mg/m(2) on day 4. 5-FU (starting dose 400 mg/m(2)) was administered as a 4-day continuous intravenous infusion with increments of 50 mg/m(2) on days 1-4. Treatment was repeated every 4 weeks. RESULTS: The MTD of the combination was found to be 600 mg/m(2) for 5-FU and 350 mg/m(2) for CPT-11. Neutropenia, febrile neutropenia and delayed diarrhea were the DLTs. Grade 3/4 neutropenia was observed in 22 (13%) out of 169 administered treatment cycles, febrile neutropenia in 7 (4%) and grade 3/4 diarrhea in 20 (12%). Other toxicities were mild. Among 36 patients evaluable for response, partial response was achieved in 8 (22%), stable disease in 12 (33%) and progressive disease in 16 (44%) patients. Responses were mostly seen at the higher dose levels. CONCLUSIONS: The combination of a 4-day continuous infusion of 5-FU followed by CPT-11 represents an active and well-tolerated regimen for patients with colorectal cancer. This regimen merits further evaluation in phase II studies.

Adult↗
PubMed2001

A phase I clinical trial of topotecan given every 2 weeks in patients with refractory solid tumors.

OBJECTIVES: Topotecan, a potent inhibitor of the enzyme topoisomerase I, has shown an interesting activity against several types of solid tumors, most notably small cell lung cancer (SCLC) and ovarian cancer. We conducted a phase I study to evaluate the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of topotecan given in a novel schedule of administration in patients with refractory solid tumors. PATIENTS AND METHODS: Twenty-six patients with histologically confirmed diagnosis of solid tumors refractory to all known forms of effective therapy were enrolled. The patients' median age was 61 years, 15 were male, and 18 had a performance status of (WHO) 0-1. Seven patients suffered from ovarian cancer, 11 from SCLC, 4 from non-SCLC, 2 from melanoma and 2 from cervical cancer. Topotecan was given for 3 consecutive days as a 30-min intravenous infusion, at doses ranging from 0.75 to 1.2 mg/m2. Treatment was repeated every 2 weeks. RESULTS: At dose level 5 with topotecan 1.2 mg/m2, both study patients presented DLTs (1 patient grade 4 neutropenia and the other grade 3 fatigue), and the recommended doses for future phase II studies are topotecan 1.1 mg/m2 for 3 consecutive days every 2 weeks. A total of 60 treatment cycles were administered, with a median of 2 cycles per patient. Grade 3/4 neutropenia was observed in 11 (18%) cycles and 2 of them were complicated by fever requiring patient hospitalization. Grade 3/4 thrombocytopenia was seen in 2 (3%) cycles and grade 3 anemia in 3 (5%). Although non-hematologic toxicity was generally mild, grade 2/3 fatigue complicated 12 (20%) cycles and grade 4 one (1.5%) requiring treatment interruption in 4 patients. Among 18 evaluable patients, no objective response to treatment was observed. CONCLUSION: This phase I study demonstrates that topotecan given at the dose of 1.1 mg/m2 for 3 consecutive days every 2 weeks is a safe and tolerable regimen and possibly permits the combination of the drug with other cytotoxic agents at clinically relevant doses.

Adult↗
PubMed2001

Oxaliplatin in combination with infusional 5-fluorouracil and leucovorin every 2 weeks as first-line treatment in patients with advanced colorectal cancer: a phase II study.

PURPOSE: To evaluate the efficacy and safety of oxaliplatin (L-OHP) in combination with leucovorin (LV)-modulated bolus plus infusional 5-fluorouracil (5-FU; de Gramont schedule) every 2 weeks in chemotherapy-naive patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Thirty-two patients (median age: 69 years) with histologically confirmed and two-dimensionally measurable metastatic CRC were enrolled. The patients' performance status (WHO) was 0 in 14 (44%), 1 in 15 (47%), and 2 in 3 (9%) patients. Twenty (62.5%) patients had at least two metastatic sites. LV was administered at a dose of 200 mg/m2/day as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at the dose of 400 mg/m2 and then, as a 22-hour continuous infusion at the dose of 600 mg/m2/day for 2 consecutive days. L-OHP was administered on day 1 at the dose of 85 mg/m2 as a 2-hour infusion in parallel with LV but using different infusion lines. Treatment was administered every 2 weeks. RESULTS: In an intention-to-treat analysis, 2 (6.2%) complete and 9 (28%) partial responses (28%; odds ratio 34.2%; 95% confidence interval 17.92-50.83%) were achieved while 8 (25%) patients had stable disease and 13 (41%) progressive disease. The median duration of response was 5 months, but the median time to progression has not yet been reached. After a median follow-up period of 11 months, the median survival has not yet been attained, but the projected probability for 1-year survival was 72%. Grade 3/4 neutropenia occurred in 16 (50%) patients while 1 (3%) of them developed febrile neutropenia. There was no treatment-related death. Peripheral neuropathy grade 2 and > or =3 occurred in 5 (16%) and 7 (21%) patients, respectively. CONCLUSIONS: The bimonthly administration of L-OHP in association with LV-modulated bolus plus infusional 5-FU ('de Gramont' regimen) is a well-tolerated and effective front-line treatment for metastatic CRC.

Actuarial Analysis↗
PubMed2000

A dose escalation study of weekly docetaxel in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of weekly administration of docetaxel for three consecutive weeks every 4 weeks in patients with advanced solid tumors. PATIENTS AND METHODS: A total of 26 patients with malignant tumors refractory to conventional treatment were enrolled in this phase I study; their median age was 62 years. Of the 26 patients, 16 (62%) had previously received more than one chemotherapy regimen and 17 (65%) had previously received taxanes in a 3-week schedule. Docetaxel was administered after appropriate premedication at escalating doses (starting dose 30 mg/m2) as a 1-h i.v. infusion for three consecutive weeks in cycles of 4 weeks. RESULTS: A total of 68 chemotherapy cycles were administered with a median of three cycles per patient (range one to six). The DLT was reached at 45 mg/m2 per week and the dose-limiting events were grade 4 neutropenia, febrile neutropenia, and treatment delay due to incomplete hematologic recovery. The MTD was defined at a dose of 42 mg/m2/week. Grade 3/4 neutropenia occurred in seven patients (27%) (10% of cycles), and four patients (15%) developed febrile neutropenia. There were no deaths due to sepsis. Grade 2 peripheral neurotoxicity was observed in two patients (8%), grade 2 and 3 fatigue in 14 (54%), grade 2 edema in seven (27%), mild allergic reactions in two (8%) and lacrimation in three (12%). One (4%) complete response and eight (35%) partial responses (overall response rate 39%) were observed in 23 evaluable patients. Stable disease and progressive disease were observed in six patients (26%) and eight patients (35%), respectively. All responses were observed in patients with metastatic breast cancer, one of whom had progressed on paclitaxel-based and two of whom had progressed on docetaxel-based chemotherapy. CONCLUSIONS: The weekly administration of docetaxel for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and can be given on an outpatient basis. Moreover, this schedule of docetaxel administration seems to have an enhanced efficacy, especially in patients with advanced breast cancer who have failed front-line taxane-based chemotherapy.

Adult↗
PubMed2000

A dose-escalation study of irinotecan (CPT-11) in combination with cisplatin in patients with advanced non-small cell lung cancer previously treated with a docetaxel-based front line chemotherapy.

PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a CPT-11 plus cisplatin combination as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-two patients with histologically confirmed NSCLC, who had failed taxotere-based front-line chemotherapy, were enrolled. The patients' median age was 61 years, 19 (86%) were male, and 17 (77%) had a performance status (World Health Organization (WHO)) 0-1. CPT-11 was administered as a 60-min i.v. infusion at a fixed dose of 100 mg/m2 on day 1 and at escalating doses on day 8, starting from 100 mg/m2 with increments of 10 mg/m2; cisplatin was administered at a fixed dose of 80 mg/m2 on day 8, 2 h after CPT-11 administration. Treatment was repeated every 3 weeks. RESULTS: At the dose of CPT-11 120 mg/m2, three out of four enrolled patients presented DLTs (grade 4 neutropenia, febrile neutropenia and delayed diarrhea); the addition of G-CSF at this level did not permit further dose-escalation. Grade 3/4 neutropenia was observed in 12 (18%) cycles, febrile neutropenia in four (6%), and grade 3/4 thrombocytopenia in four (6%). Grade 3/4 diarrhea was seen in six (29%) patients, and grade 2/3 nausea and vomiting in 12 (57%). Neurotoxicity grade 2 was observed in six (29%) patients and grade 3 in one (5%). Other toxicities were mild. The MTD was CPT-11 100 mg/m2 on day 1 and 110 mg/m2 on day 8 in combination with CDDP 80 mg/m2 on day 8. Among 12 patients evaluable for response, partial response was achieved in two (16.7%) patients and stable disease in five (41.7%). CONCLUSION: The combination of CPT-11 and cisplatin has substantial but manageable toxicity and marginal activity as salvage treatment of patients with NSCLC who have failed taxotere-based front-line chemotherapy: further investigation is warranted to define its precise role in the second-line setting.

Aged↗
PubMed2000

Docetaxel in combination with carboplatin for the treatment of advanced non-small cell lung carcinoma: a multicentre phase I study.

Docetaxel and carboplatin have shown in vitro and in vivo activity against non-small cell lung cancer (NSCLC). A phase I study was conducted in order to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of their combination. Chemotherapy-naïve patients with stage IIIB and IV NSCLC, age<75 years old, performance status (WHO) 0-2, with adequate bone marrow, renal, liver and cardiac function, were treated with docetaxel and carboplatin. Docetaxel was given at escalated doses starting from 70 mg/m(2) with increments of 10 mg/m(2) followed by carboplatin also administered at escalated doses starting from AUC 5 to 7 AUC (mg/ml. min); the regimen was administered every 3 weeks. No colony-stimulating factor or intrapatient escalation was allowed. The toxicity of the regimen was assessed during the first chemotherapy cycle. 35 enrolled patients received a total of 114 chemotherapy cycles (median 3 cycles/patient; range: 1-8). All patients were assessable for toxicity. Neutropenia was the main dose-limiting toxicity of the regimen; overall, grade 3/4 neutropenia occurred in 16 (14%) cycles; six (5%) neutropenic episodes were complicated with fever but there was no septic death. Grade 3/4 thrombocytopenia was uncommon (two cycles; 2%). Grade 3/4 diarrhoea occurred in 5 (14%) patients whilst neurotoxicity, fatigue and mucositis were extremely uncommon. Two MTDs were defined: the MTD(1) was docetaxel 80 mg/m(2) and carboplatin AUC 7 mg/ml x min whilst MTD(2) was docetaxel 100 mg/m(2) and carboplatin AUC 6 mg/ml x min. The combination of docetaxel and carboplatin is a feasible and well-tolerated outpatient regimen for the treatment of patients with locally advanced and metastatic NSCLC. This regimen merits further investigation in phase II trials.

Aged↗
PubMed2000

Front-line treatment of advanced breast cancer with docetaxel and epirubicin: a multicenter phase II study.

PURPOSE: In a previous phase I trial we evaluated the toxicity and determined the maximum tolerated doses of the docetaxel (D)-epirubicin (Epi) combination. We conducted a multicenter phase II study to evaluate the efficacy and tolerability of this regimen as front-line treatment in women with advanced breast cancer (ABC). PATIENTS AND METHODS: Fifty-four women with ABC stage IIIB (4 patients) or IV (50 patients) received front-line treatment with Epi 70 mg/m2 on day 1 and D 90 mg/m2 on day 2. The median age was 55 years, performance status (WHO) was 0-1 in 49 patients and visceral disease was present in 45 (83%). RESULTS: All patients were evaluable for toxicity and 50 for response. In an intent-to-treat analysis complete remission was observed in 5(9%) patients, partial remission in 31 (57%) (overall response rate 66%, 95% confidence interval: 54% 79%), stable disease in 9 (17%) and disease progression in 9 (17%). After a median follow-up of 11.5 months, the median duration of responses was 8 months, the median time to disease progression 11.5 months and the median survival has not yet been reached. The probability of one-year survival was 65%. Three hundred six cycles of treatment were administered (median 6 cycles per patient). Grade 3 and 4 neutropenia was observed in 8 (15%) and 31 (57%) patients, respectively, and febrile neutropenia in 19 (35%). Prophylactic rh-G-CSF was used in 45 (83%) patients or 226 (74%) cycles. Other hematologic or non-hematologic toxicities were usually mild. In five (9%) patients the left ventricular ejection fraction (LVEF) was decreased by more than 10% with the treatment. Two patients died during the treatment of respiratory failure without associated neutropenia. CONCLUSIONS: The combination of docetaxel epirubicin is an effective and well tolerated front-line treatment in patients with ABC.

Adult↗
PubMed2000

Salvage treatment of advanced non-small-cell lung cancer previously treated with docetaxel-based front-line chemotherapy with irinotecan (CPT-11) in combination with cisplatin.

BACKGROUND: A phase II study was conducted in order to determine the toxicity and efficacy of the combination of CPT-11 and cisplatin, as salvage treatment in patients with advanced non-small-cell lung cancer (NSCLC), progressing after a docetaxel-based front-line regimen. PATIENTS AND METHODS: Thirty-one patients (median age 61 years) with NSCLC, were enrolled. Twenty-six (84%) patients were male, twenty-five (81%) had disease stage IV, and twenty-eight (90%) had a performance status (WHO) 0-1. CPT-11 was administered as a 60-minute i.v. infusion at the dose of 100 mg/m2 on day 1 and 110 mg/m2 on day 8; cisplatin was administered at the dose of 80 mg/m2 on day 8, after CPT-11 administration. Treatment was repeated every three weeks. RESULTS: A total of 110 chemotherapy cycles were administered. In an intention-to-treat analysis 7 patients (23%; 95%) Introduction confidence interval (95% CI): 8%-37%) achieved a partial response, 6 (19%) had stable disease, and 18 (58%) progressive disease. Three of responders had failed a previous docetaxel-carboplatin combination. The median duration of response was 3 months, the median TTP 8 months and the median survival for the entire group 8 months. Grade 3-4 neutropenia was observed in 16 (52%) patients and in two cases this was febrile. Grade 3 and 4 thrombocytopenia occurred in two (7%) patients, respectively. Grade 3 and 4 diarrhea was seen in 10 (33%) patients, grade 2-3 neurotoxicity in 2 (6%), and fatigue grade 2-3 in 12 (39%). Other toxicities were mild. CONCLUSIONS: The combination of CPT-11 and cisplatin has manageable toxicity and interesting activity as salvage treatment of patients with advanced NSCLC, previously treated with a docetaxel-based front-line regimen.

Aged↗
PubMed2000

Frontline treatment of advanced gastric cancer with docetaxel and granulocyte colony-stimulating factor (G-CSF): a phase II trial.

We conducted a phase II study to evaluate the efficacy and tolerance of docetaxel monotherapy with granulocyte colony-stimulating factor (G-CSF) support in patients with advanced gastric cancer. Thirty patients with measurable advanced gastric cancer were enrolled. Twenty-four patients were chemotherapy-naive and six patients had previously received adjuvant chemotherapy after complete surgical resection. Docetaxel was administered at 100 mg/m2 IV during 1 hour every 3 weeks. G-CSF 5 microg/kg SC was also given on days 2 through 8 prophylactically to all patients. All patients were evaluable for response and toxicity. We observed one complete and five partial responses for an overall response rate of 20% (95% confidence interval: 6-34%). In addition, seven patients (23%) had stable disease. After a median follow-up time of 7 months, the median duration of response was 4.5 months, the median time of tumor progression was 6 months, and the median survival was 7 months. The estimated probability of 1-year survival was 28%. Toxicity was generally mild. Grade III/IV neutropenia occurred in 11 (36%) patients. Neutropenia with fever developed in three patients (10%). There were no toxic deaths. Docetaxel with G-CSF support is an active drug and well tolerated by patients with advanced gastric cancer. Docetaxel merits further investigation in combination with other active agents as frontline treatment in patients with advanced gastric cancer.

Adenocarcinoma↗
PubMed2000

Phase I study of the gemcitabine/oxaliplatin combination in patients with advanced solid tumors: a preliminary report.

The purpose of this study was to determine the maximum tolerated dose and evaluate the dose-limiting toxicities of the gemcitabine/oxaliplatin combination in patients with advanced-stage solid tumors. Of the 48 enrolled patients, 35% had first-line, 23% had second-line, and 42% had third-line therapy. Patients received escalating doses of 1,000 to 1,600 mg/m2 gemcitabine on days I and 8 plus 60 to 120 mg/m2 oxaliplatin on day 8, every 21 days. The dose-limiting toxicities (first nine dose levels) were grade 4 neutropenia, grade 3 asthenia, and grade I to 3 neutropenia or thrombocytopenia. One hundred fifty-three cycles have been administered without any febrile neutropenia or toxic death. Grade 3-4 neutropenia and grade 3 thrombocytopenia were noted in 13 (9%) and seven (5%) cycles, respectively. Nonhematologic toxicity has been mild; the most common was grade 2 to 3 asthenia occurring in 29% of cycles. Among 30 evaluable patients, four partial responses have been observed (response rate, 13%). In this phase I study, the maximum tolerated dose of this drug combination has not yet been reached, although gemcitabine up to 1,600 mg/m2 (days I and 8) plus oxaliplatin up to 120 mg/m2 (day 8) was active and well tolerated, warranting further evaluation in phase II studies.

Aged↗
PubMed1999

Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: a multicenter phase II trial. Greek Breast Cancer Cooperative Group.

PURPOSE: The activity of the docetaxel-gemcitabine combination in women with disease progression after initial chemotherapy for metastatic breast cancer (MBC) was investigated in a multicenter phase II study. PATIENTS AND METHODS: Fifty-two patients with metastatic breast cancer who had disease relapse or progression after completion of an anthracycline-based front-line regimen were treated with gemcitabine 900 mg/m2 on day 1 and day 8 and docetaxel 100 mg/m2 on day 8. G-CSF 150 mucg/m2/d s.c. was given from day 9 to day 16 and the treatment was repeated every three weeks. The patients' median age was 57 years and the performance status (WHO) was 0 for 26, 1 for 20 and 2 for 6 patients. The treatment was second-line for 27 (52%) and > or = third-line for 25 (48%) patients. All patients were evaluable for response and toxicity. RESULTS: Complete response occurred in seven (14%) patients and partial response in 21 (40%) for an overall response rate of 54% (95% confidence interval (95% CI): 40%-67%). Fifteen (29%) patients had stable disease and nine (17%) progressive disease. Of 25 patients previously treated with taxanes. 11 (44%) responded (1 CR, 10 PR). Interestingly, in four patients with disease progression while receiving docetaxel or paclitaxel monotherapy, the docetaxel + gemcitabine combination achieved partial responses. Responses were observed at all metastatic sites (local disease 62%, lymph nodes 58%, skin 44%, lung 47% and liver 36%) with a median duration of response of 3.6 months (range 1-16) and a median time to disease progression of eight months (range 2-18.5). Grade 3 neutropenia developed in 10 (19%) and grade 4 in five (10%) patients. Neutropenia was associated with infection in four patients without toxic deaths. Grade 3 thrombocytopenia developed in nine (17%) patients and grade 4 in two (4%). Non-hematologic toxicity was usually mild. CONCLUSION: The docetaxel-gemcitabine combination is an active and well tolerated salvage treatment in patients with MBC. Previous treatment with taxanes does not preclude a good clinical response to this regimen.

Adult↗
PubMed1999

Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: a multicenter dose-escalation study. The Greek Breast Cancer Cooperative Group (GBCCG).

PURPOSE: To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer. PATIENTS AND METHODS: Forty-seven chemotherapy-naïve metastatic breast cancer patients aged < 75 years with PS (WHO) 0-2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0-1, 16 (34%) were premenopausal and 25 (53%) had visceral disease. RESULTS: When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3-4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1-2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%-69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached. CONCLUSIONS: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.

Adult↗
PubMed1999

A technique for dual determination of cytotoxic and helper lymphocyte precursor frequency by a miniaturized dye release method.

Helper (HTLPf) and cytotoxic (CTLPf) lymphocyte precursor frequency assays are increasingly used in bone marrow stem cell and organ transplant compatibility testing. Current techniques require large cell numbers and radioisotopes. To improve the technique, we developed a miniaturized fluorescent read-out combined HTLPf/CTLPf limiting dilution assay. The assay requires only 5 x 10(6) stimulators, 2 x 10(6) responders and 0.24 x 10(6) target cells in Terasaki plates (40 microl/well). For the HTLPf, culture supernatants from each well were assayed for IL-2 production. The IL-2-dependent proliferation of the mouse 9.12 cell line was detected by a semi-automated fluorescent dye technique. After addition of rhIL-2 (recombinant human IL-2) on days 3 and 7, CTLPs were detected on day 10 by measuring the lysis of dye-labeled targets. Results were comparable to standard radioisotope-based techniques. The assay had a coefficient of variation of approximately 30%. The assay detected helper CD4 cells, pure cytotoxic CD8, helper CD8 cells and helper/cytotoxic CD8 cells. Discrimination was demonstrated between HLA-matched related and non-related pairs. The ease of testing and small cell numbers required should facilitate further evaluation of HTLPf and CTLPf for compatibility testing in unrelated donor transplantation and monitoring immune responses following adoptive transfer of lymphocytes.

Animals↗
PubMed1999

High-dose corticosteroid therapy for diffuse alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients.

In a series of 74 patients with hematological malignancies undergoing allogeneic bone marrow or peri- pheral blood stem cell transplants from an HLA-identical sibling donor, four developed diffuse alveolar hemorrhage (DAH) between days 0 and 23 post transplant. Diagnosis was made by the radiographic finding of diffuse bilateral lung opacities, and bloody lavage fluid on bronchoscopy. Two patients required mechanical ventilatory support. They were treated with methylprednisolone 0.25-1.5 g/day for at least 4 days with slow tapering thereafter. All patients showed an immediate response and two became long-term survivors with normal respiratory function. Two had a relapse of DAH, developed acute respiratory distress syndrome (ARDS) and died with multi-organ failure. Risk factors for DAH were one or more courses of intensive chemotherapy pretransplant vs no treatment or low-dose chemotherapy (4/4 DAH vs 23/70 no DAH; P = 0.015), and second transplants (2/2 DAH vs 1/70 with no DAH; P = 0.006). These results indicate that DAH is life-threatening but is potentially reversible by prompt treatment with high doses of steroids.

Adult↗
PubMed1999

Human G-CSF-mobilized CD34-positive peripheral blood progenitor cells can stimulate allogeneic T-cell responses: implications for graft rejection in mismatched transplantation.

To investigate mechanisms of stem cell graft rejection we studied the allo-stimulatory potential of G-CSF mobilized peripheral blood progenitor cells (PBPC). CD34+ cells were purified (>95%) in a two-step procedure using immunoaffinity columns for CD34 selection and T-depletion. The capacity of CD34+ cells to stimulate allogeneic T-cell responses was compared with other cells from the same individual. CD34+ cells induced potent proliferative responses at stimulator:responder ratios of 1:20, but were approximately 50-fold less efficient compared to dendritic cells. Furthermore, CD34+ cells primed responses from partially matched allogeneic T cells in bulk cultures. Dual-colour flow cytometry showed that the co-stimulatory molecules B7.1, CD40 and ICAM-1 were absent on resting CD34-positive progenitor cells, but were induced during incubation with allogeneic lymphocytes due to a cytokine-mediated effect. Up-regulation of accessory molecules on CD34+ cells was reproduced by incubation with interferon-gamma or GM-CSF which enhanced the allo-stimulatory activity of CD34+ cells. Blocking studies with inhibitory antibodies suggested co-stimulatory functions for B7.2, ICAM-3, CD40 and LFA-3. CD34+ cells were more efficient in inducing allogeneic T-cell responses when compared to the unprocessed leukapheresis products. The reduced allo-stimulatory ability of G-CSF mobilized PBPC could be explained by the presence of CD3+ 4+ and CD3+ 8+ lymphocytes with suppressor activity. We conclude that current methods of stem cell selection for transplantation do not avoid allosensitization of the recipient and that further graft manipulation with add-back of lymphocytes or selection of subsets of CD34+ cells with reduced allo-stimulatory ability may reduce graft rejection.

Antibodies, Blocking↗
PubMed1999

Dose-escalation study of docetaxel in combination with mitoxantrone as first-line treatment in patients with metastatic breast cancer.

PURPOSE: To define the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with mitoxantrone in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one chemotherapy-naive patients with MBC (median age, 61 years) were enrolled. Thirty-eight (93%) had performance status (World Health Organization [WHO]) 0, 29 (71%) were postmenopausal, and 21 (51%) had estrogen receptor-negative tumors. Patients received escalated doses of docetaxel (75 to 100 mg/m2) on day 1 and mitoxantrone (8 to 22 mg/m2) on day 8. Treatment was repeated every 3 weeks. RESULTS: A total of 217 chemotherapy cycles were administered. Without recombinant human granulocyte colony-stimulating factor (rhG-CSF) support, the MTD1 occurred at the first dose level (docetaxel 75 mg/m2 and mitoxantrone 8 mg/m2); DLTs were febrile neutropenia, grade 4 neutropenia lasting more than 5 days, and grade 3 diarrhea. With prophylactic rhG-CSF, the MTD2 was docetaxel 100 mg/m2 and mitoxantrone 20 mg/m2; DLTs were febrile neutropenia and grade 4 neutropenia. Nine (22%) patients developed neutropenia after the first cycle of treatment. A total of 19 episodes of febrile neutropenia (9% of the cycles) occurred during the whole period of the study; there were no toxic deaths. At high docetaxel (100 mg/m2) and mitoxantrone (> 12 mg/m2) dose levels, a significant decrease of the absolute lymphocyte number was observed; immunophenotyping revealed that all lymphocyte subpopulations were reduced. Grades 2 and 3 neurosensory toxicity occurred in six patients (15%) and one patient (2%), respectively. No cardiac toxicity was observed. Nine complete responses (22%) and 23 partial responses (56%) were achieved (overall response rate, 78%; 95% confidence interval, 62.5% to 88.8%). The median duration of response was 12.5 months, and the median time to tumor progression was 14.5 months. CONCLUSION: The reported combination of docetaxel and mitoxantrone with G-CSF support is a safe, intensified, well-tolerated, and effective regimen as first-line treatment in patients with MBC.

Adult↗