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1.
SB Kaye M Piccart M Aapro P Francis J Kavanagh 《Canadian Metallurgical Quarterly》1997,33(13):2167-2170
Docetaxel (Taxotere) has been studied at a dose of 100 mg/m2 i.v. as a one hour infusion every 3 weeks, in four phase II trials in patients with extensively pretreated ovarian cancer. A total of 340 patients were treated, including 256 patients in two separate EORTC (European Organization for Research and Treatment of Cancer) trials and 84 patients in two trials in the U.S.A. All patients had received prior cisplatin or carboplatin therapy and the treatment-free interval was less than 4 months in 155 patients. The overall response rate using conventional UICC criteria was 30% among 315 evaluable cases (95% confidence interval: 24-36%). Among 155 patients whose disease was most refractory (i.e. treatment-free interval was less than 4 months), the overall response rate was 28% (95% confidence interval: 19-36%). Response duration ranged from 4 to 17 months. Grade IV neutropenia was a common finding and fluid retention was observed. The incidence of febrile neutropenia ranged from 8 to 44% of patients with two deaths (i.e. 0.6% of the total treated) related to neutropenic sepsis. Docetaxel and paclitaxel (Taxol) have comparable activities in ovarian cancer. Ongoing studies with docetaxel include its use in patients as part of first-line therapy, as well as in patients refractory to paclitaxel. To prevent the development of fluid retention, these now involve the routine use of steroid prophylaxis. It is expected that docetaxel will prove to be an important addition to the drugs available for the treatment of ovarian cancer. 相似文献
2.
V Valero SE Jones DD Von Hoff DJ Booser RG Mennel PM Ravdin FA Holmes Z Rahman MW Schottstaedt JK Erban L Esparza-Guerra RH Earhart GN Hortobagyi HA Burris 《Canadian Metallurgical Quarterly》1998,16(10):3362-3368
PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel. 相似文献
3.
U Vanhoefer S Cao A Harstrick S Seeber YM Rustum 《Canadian Metallurgical Quarterly》1997,8(12):1221-1228
BACKGROUND: Multidrug resistance has been associated with expression of the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer and non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies of paclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP. MATERIALS AND METHODS: Athymic nude mice (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analysis) were treated with the maximum tolerated doses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50 mg/kg three-hour i.v. infusion), or docetaxel ([DC] 40 mg/kg three-hour i.v. infusion). In vitro, the activity of doxorubicin, paclitaxel and docetaxel was evaluated by the sulphorhodamine B (SRB) assay using the pyridine analogue PAK-104P (5 microM), a potent inhibitor of MRP-function. RESULTS: At their MTDs both taxoids showed significant activity against MRP-negative HT1080 xenografts with response rates of 80% (40% CR) for PC and 100% (60% CR) for DC. In contrast, DC was significantly more active than PC in nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tumor xenografts (overall response rates: 100% (60% CR) for DC; 10% (0% CR) for PC; 0% for Dx). Since treatment of mice with the MTD of PC or DC yielded similar overall toxicity (maximum weight loss for HT1080: PC 8.6 +/- 2.2%; DC 7.5 +/- 2.2% and for HT1080/DR4: PC 11.6 +/- 3.0%; DC 7.6 +/- 1.8%, respectively), these results demonstrate the increase in the therapeutic index for docetaxel against MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold, 6.4-fold and 2.8-fold more resistant than parental cells to doxorubicin, PC and DC, respectively. Pyridine analogue PAK-104P completely restored drug sensitivity to PC and DC, while no effect of PAK-104P on parental HT1080 cells was observed. CONCLUSIONS: Both taxoids, when given at their MTDs, showed significant efficacy against parental HT1080 tumor xenografts. However, docetaxel at its MTD was significantly more active against MRP-expressing tumor xenografts than paclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higher for PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restored sensitivity to both taxoids, the observed resistance appears to be related to MRP. These data suggest, that docetaxel is not as readily transported by MRP as paclitaxel leading to an increased therapeutic ratio in MRP-expressing tumors in vivo. Therefore, docetaxel may have therapeutic advantages in the clinical treatment of MRP-expressing tumors. 相似文献
4.
Paclitaxel and docetaxel are 2 compounds from the new taxoid class of anti-cancer agents. Both drugs are very similar in preclinical activity, mechanism of action and spectrum of clinical activity. Some subtle differences in the intracellular retention of docetaxel may account for its lack of schedule-related myelosuppression and greater potency, and may be relevant to the skin toxicity and oedema which it produces. Early data suggest that there may be differing behaviour of anthracycline/taxoid combinations with respect to cardiotoxicity. Paclitaxel has been studied in several first-line combination therapy trials in ovarian cancer. Here, paclitaxel in combination with a platinum compound seems to have proven itself as a standard regimen. It is uncertain if docetaxel will be evaluated in this context. An abundance of clinical data is available for both analogues in the advanced, metastatic setting of breast cancer. Both also have been compared as single agents with doxorubicin with the results suggesting paclitaxel in a 3-hour infusion is inferior to the anthracycline (in terms of response rate), and those of docetaxel suggesting it is superior to the same dose of doxorubicin. This indirect comparison favours the activity of docetaxel; however, it is clear that in the dose/schedules studied, the taxoid compounds are not equitoxic. Either agent by itself, in the treatment of metastatic breast cancer, remains appropriate; however, lack of cumulative toxicity may make paclitaxel more attractive in some situations where prolonged administration is foreseen. Lung cancer trials have also confirmed the activity of both agents, although docetaxel appears to have slightly more promising activity in previously treated patients than paclitaxel. Paclitaxel in combination with cisplatin has been evaluated in randomised trials as first-line treatment of non-small-cell lung cancer (NSCLC). The results of these trials taken together suggest that this combination has an impact on survival similar to other new regimens now considered 'standard' in the front-line setting in this disease. Unfortunately, despite all the phase II data generated in numerous tumour types, little else can be said about the role of either taxoid in the 'standard' management of malignant disease. It will be some years yet before taxoid-based combinations have been evaluated sufficiently in randomised trials such that the impact of this novel class can be adequately assessed in terms of survival and cure rates. 相似文献
5.
E Saksela 《Canadian Metallurgical Quarterly》1998,37(6):533-537
Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer. 相似文献
6.
B Velikson P Cohen M Rholam JP Rose BC Wang JC Smith 《Canadian Metallurgical Quarterly》1998,11(10):909-916
This article reviews the information currently available on the pharmacoeconomic profile of taxanes in ovarian cancer. Because paclitaxel is the only taxene approved for this clinical indication, our overview is almost entirely focused on the cost-effectiveness profile of this drug. In advanced ovarian cancer, first-line regimens based on paclitaxel have been reported to be more effective than standard therapy based on cyclophosphamide + cisplatin. The improved survival with paclitaxel and the increased cost induced by this drug have prompted a series of pharmacoeconomic analyses, the results of which are summarized and discussed. Three studies, published between 1996 and 1997, calculated the cost per life-year gained using paclitaxel + cisplatin as opposed to cyclophosphamide + cisplatin. The estimates of survival gain and increased expenditure using paclitaxel were very similar; consequently, the results produced by these three analyses were homogeneous with values of cost per life-year gained around $20000. Because this value is below the conventional limit of $50000, the pharmacoeconomic results on paclitaxel suggest a favorable cost-effectiveness profile. Docetaxel is another taxane proposed for the treatment of advanced ovarian cancer; however, the drug has not yet been approved for this clinical indication and so a pharmacoeconomic assessment on this agent is still premature. 相似文献
7.
R Hájek 《Canadian Metallurgical Quarterly》1996,135(12):393-396
The paclitaxel (TAXOL); Bristol-Myers Squibb Company) represents first agent from novel class of antineoplastic drugs--taxanes to enter routine clinical practice. Paclitaxel interferes with microtubular polymerization by promoting abnormal assembly of microtubules and inhibiting their subsequent disassembly. Pharmacokinetics of paclitaxel has been intensively studied. There are indications for nonlinear pharmacokinetics when paclitaxel is administered as a short infusion and at higher doses. Neurotoxicity, mucositis, and leukopenia correlate with some pharmacokinetic parameters. The clinical development of paclitaxel was initially hampered by hypersensitivity reactions. Current dosage regiments with premedication reduced the incidence of these events to 3%. The major dose-limiting adverse effect of paclitaxel is neutropenia. Significant activities were reported especially in patients with advanced ovarian, breast, non-small cell lung cancer (NSCLC), head and neck cancer and in other types of tumours. Long-term follow-up will also allow the effects of the drug on patient survival to be determined. At present combination of Taxol (paclitaxel) with cisplatin clearly improves the duration of progression-free survival and of overall survival compared with cyclophosphamide and cisplatin in women ovarian cancer. Recently was TAXOL (paclitaxel) registered in Czech republic for treatment of patients with advanced metastatic ovarian carcinoma and in patients with metastatic breast cancer after failure of the standard therapy. 相似文献
8.
The topoisomerase I inhibitor topotecan has shown antitumour activity against a variety of tumour types in vitro and in vivo. Topotecan in combination with drugs that induce DNA damage generally results in synergistic killing of tumour cells in vitro. As the activity of topotecan is related to exposure time, the drug is administered by intravenous infusion either continuously or once daily over a 30-minute period for several consecutive days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks produced response rates of up to approximately 20% in patients with advanced ovarian cancer who had failed to respond to platinum-based regimens or relapsed after initial response to such regimens. No significant differences in efficacy were apparent between topotecan and paclitaxel in a phase III study in patients with recurrent ovarian cancer, although a trend in favour of topotecan was evident for all major efficacy parameters. Non-cumulative myelosuppression, including neutropenia, thrombocytopenia and anaemia, is the dose-limiting toxicity associated with topotecan. Myelo-suppression was significantly more common with topotecan than with paclitaxel in a single comparative study. Non-haematological adverse events in topotecan recipients are generally mild and include alopecia, nausea, vomiting, and other gastrointestinal problems. Thus, topotecan has modest efficacy in the treatment of recurrent advanced ovarian cancer, with clinical activity similar to that of paclitaxel in a large randomised phase III study in this setting. Combinations of paclitaxel and a platinum compound are being used increasingly for first-line therapy, although relapse rates remain significant. Topotecan is therefore a suitable second-line option, providing antitumour response for some patients whose disease has relapsed after, or is refractory to, platinum-based therapy. Its wider potential when used either alone or in combination regimens should become clearer from ongoing studies. 相似文献
9.
Relevant data from direct comparisons in clinical trials are not available for economic evaluations of docetaxel and paclitaxel in the management of metastatic breast cancer. A modified Markov model is used to estimate the incremental cost in US$ per quality-adjusted life-year (QALY) for docetaxel versus paclitaxel in managing metastatic breast cancer patients in the US. The model incorporates the latest available clinical trial data (response rates of 47.8% for docetaxel and 25% for paclitaxel, chemotherapy-specific toxicities, time to progression, and 1-year survival) from studies against other comparators. Medical care resources were estimated by US oncologists and costed using US data sources. Utility scores were obtained from 29 US oncology nurses. The base case and subsequent sensitivity analyses show that docetaxel management of advanced breast cancer is more costly per patient but yields higher health benefits than paclitaxel therapy. The cost per QALY gained by docetaxel is $8615, and ranges between $3943 and $9416 in sensitivity analyses. These results confirm those of an earlier model using preliminary data and compare favorably with other cost-utility results in this patient group. 相似文献
10.
PURPOSE: To determine the potential economic and policy implications that result from incorporating paclitaxel into first-line therapy for stage 3 and 4 ovarian cancer patients in the province of Ontario, Canada. METHODS: A cost-effectiveness analysis was conducted to compare cisplatin/cyclophosphamide (CC), a standard therapy, with cisplatin/paclitaxel (CT). Based on survival curves from a clinical trial, mean costs and survival were calculated. Sensitivity analyses were conducted based on altering the duration of paclitaxel infusion, discount rates, and efficacy of paclitaxel. RESULTS: The mean survival duration is prolonged from 2.06 years with the standard therapy to 2.44 years with the paclitaxel combination. The paclitaxel therapy is more expensive, with a mean cost of $17,469 (Canadian) per patient treated with CT compared with $5,228 per patient with CC. The incremental cost-effectiveness ratio is $32,213 per year gained. Sensitivity analyses show that the conclusions remain unchanged. The use of CT as first-line treatment for advanced ovarian cancer patients in Ontario requires an additional $9 million per year over and above the present costs to treat this patient population. CONCLUSION: Although paclitaxel-based therapy prolongs survival, it comes at an increased cost. It may not be possible to fund paclitaxel treatment using resources presently allocated to first-line chemotherapy for advanced ovarian cancer. The policy implications for absorbing the cost of paclitaxel in the context of a publicly funded health care system are discussed. 相似文献
11.
A Younes J Romaguera O Mesina F Hagemeister AH Sarris MA Rodriguez P McLaughlin HA Preti C Bachier F Cabanillas 《Canadian Metallurgical Quarterly》1998,103(3):678-683
Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h (50 mg/m2/d). 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL. 相似文献
12.
R Kreienberg 《Canadian Metallurgical Quarterly》1998,87(17):573-577
Treatment of anthracycline-resistant metastatic breast cancer with new antineoplastic agents remains a challenge for the next future. The 5-year survival for this disease is only 15%, and hormonal and chemotherapeutic options remain essentially palliative. New treatment drugs or drug combinations are urgently needed to improve the prospects for patients with metastatic breast cancer, particularly for those with disease characteristics indicating a particularly poor prognosis. Taxanes are promising new drugs and have shown encouraging activity in patients with disease resistant to anthracyclines and in patients with visceral metastases, both with a poor prognosis. Paclitaxel (taxol) is applied with a dose of 175 mg/m2 in a 3 hour infusion and docetaxel (taxotere) with a dose of 100 mg/m2 q 3 weeks. Remission rates are expected between 6-30% for taxol and between 29-48% for docetaxel. Highly active in patients with anthracycline-resistant disease appears to be the vinca-alkaloid vinorelbine too. In patients treated with adriamycin objective remissions between 15-33% can be obtained. The long time known 5-fluorouracil comes to the third place of the effective drugs. Continuous infusion or addition of folic acid increases the intracellular efficacy and results in 5-53% objective remissions. In second-line chemotherapy platin-analogues together with etoposide, vincristine and 5-FU achieve partial or complete remissions between 19-37% for cisplatin containing and 5-12 for carboplatin containing combinations. This may eventually play a role especially if three drug combinations containing paclitaxel, epirubicin and vinorelbine will be used, which are reported to result in 20-33% complete response rates and 66% objective response. The indication for other new drugs like tomudex, topoisomerase-I-inhibitor and gemcitabine for anthracycline-resistant breast cancer remains to be established in multicenter studies. 相似文献
13.
M Markman PG Rose E Jones IR Horowitz A Kennedy K Webster J Belinson N Fusco L Fluellen B Kulp G Peterson WP McGuire 《Canadian Metallurgical Quarterly》1998,16(5):1849-1851
PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question. 相似文献
14.
J Markowska 《Canadian Metallurgical Quarterly》1997,68(11):554-557
The paclitaxel/cisplatin regimen is superior to standard therapy PC based on higher overall response rates, higher negative second-look laparotomy rate and overall survival. The regimen paclitaxel/cisplatin/cyclophosphamide seem to give the best treatment results. Interval debulking surgery after initial laparotomy and intraperitoneal therapy with cisplatin and i.v. cyclophosphamide in patients with residual disease improve overall survival rate. 相似文献
15.
Although small-cell lung cancer (SCLC) represents only 20% of all lung cancer cases in the United States, it is the most lethal subtype. Combination chemotherapy unequivocally offers the best chance for improved survival in SCLC. Either PE (platinum plus etoposide) or CAV (cyclophosphamide, Adriamycin, and vincristine) is a reasonable first-line therapy. Alternating PE with CAV does not appear to be significantly superior to PE or CAV alone. Increasing dose intensity, although sometimes associated with higher response rates, does not appear to significantly improve survival and should not be used outside of a clinical study. Several new agents with novel mechanisms of action show promise in treating SCLC. These include: gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), topotecan (Hycamtin), and irinotecan (Camptosar). Given the poor survival and response rates in relapsed patients and the chemoresponsiveness of SCLC, patients with newly diagnosed extensive disease should be encouraged to enroll in phase I or II trials. Thoracic radiotherapy confers a small survival advantage in limited-stage SCLC patients. Although prophylactic cranial irradiation does not significantly improve survival, it does reduce central nervous system (CNS) recurrences with minimal long-term sequelae. Surgery should be considered only for: (1) resection of a solitary pulmonary nodule, which must be followed by adjuvant chemotherapy; and (2) resection of an unresponsive chest tumor, which may harbor a non-small-cell lung cancer component. 相似文献
16.
MA Morgan EA Stadtmauer SM Luger DL Porter PA Mangan P O'Neil S Kamelle I Benjamin R Mick SA King SC Rubin 《Canadian Metallurgical Quarterly》1997,67(3):272-276
OBJECTIVE: The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. METHODS: Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m2), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m2) and cyclophosphamide (1.5 g/m2 with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m2 every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. RESULTS: Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0-35%). CONCLUSION: Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients. 相似文献
17.
MT Huizing LJ van Warmerdam H Rosing MC Schaefers A Lai TJ Helmerhorst CH Veenhof MJ Birkhofer S Rodenhuis JH Beijnen WW ten Bokkel Huinink 《Canadian Metallurgical Quarterly》1997,15(5):1953-1964
PURPOSE: To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients. PATIENTS AND METHODS: Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study. RESULTS: The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models. CONCLUSION: The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found. 相似文献
18.
M Markman 《Canadian Metallurgical Quarterly》2003,5(6):454-458
A recently reported randomized trial has demonstrated that administration of single-agent paclitaxel to women with advanced ovarian cancer who attain a clinically defined complete response to platinum/paclitaxel-based chemotherapy can substantially improve progression-free survival. Whether this strategy will improve overall survival in this clinical setting remains uncertain. 相似文献
19.
Lingqin Song Yinbin Zhang Jianjun He Xijing Wang Hongbing Ma Wentao Xi Liang Liang 《Canadian Metallurgical Quarterly》2011,10(7)
Objective: The aim of this study was to investigate the side effects of docetaxel with cyclophosphamide as postoperative adjuvant chemotherapy for elderly breast cancer patients. Methods: Thirty-six operable elderly breast cancer patients at intermediate risk based on the St Gallen risk classi.cation underwent modified radical mastectomy and then were given four cycles of TC regimen (docetaxel 75 mg/m2 i.v. on day 1; cyclophosphamide 600 mg/m2 i.v. on day 1; every 21 days ). Primary prophylaxis granulocyte colony stimulating factor (G-CSF) 200μg i.h. was administered on day 4-6. Results: The main side effect was neutropenia. Grade 3 neutropenia developed in 36.1% and G4 in 19.4%, respectively. Most of the other side effects were G1-2. Dose reduction occurred in 11.1% patients. The completion rate of chemotherapy was 100%. Conclusion:Docetaxel with cyclophosphamide as postoperative adjuvant chemotherapy regimen with G-CSF primary prophylaxis is tolerable for elderly patients in general good condition. 相似文献
20.
G Nanjangud KN Naresh CN Nair B Parikh PH Dixit SH Advani PS Amare 《Canadian Metallurgical Quarterly》1998,106(1):37-43
BACKGROUND: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin-paclitaxel. DESIGN: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients. PATIENTS AND METHODS: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m2 followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg x ml-1 x min. RESULTS: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%-54%). Response rates for platinum-refractory patients and those with early (> or = 3 and < 12 months) and late (> 12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy. CONCLUSION: This combined paclitaxel-carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy. 相似文献