紫杉醇联合蒽环类药物治疗晚期乳腺癌的临床观察

目的观察紫杉醇联合吡柔比星(THP)/表阿霉素(E-ADM)治疗晚期乳腺癌患者的临床疗效和不良反应.方法95例患者均为晚期乳腺癌,化疗方案为THP 50 mg/m2或E-ADM70 mg/m2,快速静滴15 min,d1;国产紫杉醇135～175 mg/m2,静滴3 h,d2.21 d为一个周期,连用2个周期以上评价疗效.结果全组95例均可评价疗效,总有效率为40.0%.完全缓解率为15.8%,部分缓解率为24.2%.无治疗相关死亡,主要不良反应为骨髓抑制和脱发.THP组脱发发生率较EADM组少,差异有显著性.结论紫杉醇联合THP/E-ADM化疗晚期乳腺癌缓解率较高,不良反应可耐受,是治疗晚期乳腺癌安全有效的化疗方案.     

Phase I combination trial of gemcitabine,paclitaxel, and carboplatin in patients with advanced malignancy

PURPOSE. We performed a phase I trial of carboplatin and paclitaxel in combination with gemcitabine in order to determine the tolerability of this triplet. METHODS. Enrolled in the study were 26 patients with advanced cancer, most with non-small cell lung cancer. The patients received escalating doses of carboplatin and paclitaxel on day 1 and gemcitabine (30-min infusion) on days 1, 8, and 15 of a 28-day treatment cycle. The doses of each drug ranged from an area under the concentration-time curve (AUC) of 5 to 6 for carboplatin, 135 to 175 mg/m(2) for paclitaxel, and 300 to 1000 mg/m(2) for gemcitabine. RESULTS. Hematologic toxicity was the most commonly observed toxicity and was dose-limiting. During the first cycle at the recommended phase II dose, there were two instances of grade 4 neutropenia and one instance of grade 4 thrombocytopenia among six patients, none of which was dose-limiting. Cumulative hematologic toxicity emerged in subsequent cycles. Non-hematologic toxicities were mild. Five patients, all with previously untreated non-small-cell lung cancer (NSCLC), had a partial response. Nine patients with NSCLC or upper gastrointestinal malignancies experienced stable disease. CONCLUSIONS. Based on significant neutropenia and thrombocytopenia, the regimen recommended for further study consists of carboplatin AUC 5, paclitaxel 175 mg/m(2), and gemcitabine 1000 mg/m(2) on a 28-day cycle. The antitumor activity noted suggests that further investigation of this well-tolerated combination in specific tumor types, especially NSCLC, is warranted.     

紫杉醇联合铂类与放疗同步治疗局部晚期食管癌的临床研究

目的探讨常规剂量紫杉醇联合铂类与放疗同步治疗食管癌的疗效,以及扩大照射野对同步放化疗疗效的影响。方法89例局部晚期食管癌初治患者,采用根治性同步放化疗,扩大野组51例,常规野组38例。放疗总剂量60 Gy(分两阶段进行),放疗的第1周和第4周给予常规剂量的紫杉醇和铂类化疗。结果87.6%的患者完成了治疗计划,扩大野组和常规野组的治疗有效率分别为75.5%和66.7%(P=0.37)。两组的Ⅲ级以上急性毒副反应主要为白细胞、血小板下降和放射性食管炎,主要远期放射损伤为肺纤维化,两组间各种毒副反应发生率差异均无统计学意义。患者总的3年生存率为32.8%,3年无复发转移生存率为34.5%,3年局部控制率为44.0%;扩大野组和常规野组的3年生存率、3年无复发转移生存率、3年局部控制率之间差异均无统计学意义。完成治疗计划的Ⅱ、Ⅲ期患者中,扩大野组3年生存率、3年无复发转移生存率及3年局部控制率较常规野组显著提高。结论常规剂量紫杉醇联合铂类化疗同步扩大野放疗对食管癌患者是安全的,可增加Ⅱ、Ⅲ期食管癌患者的局部控制率,提高3年生存率。     

Doxorubicin and paclitaxel in advanced breast carcinoma: importance of prior adjuvant anthracycline therapy

BACKGROUND: The authors undertook a Phase II multicenter trial to assess the efficacy and toxicity of doxorubicin and paclitaxel in combination in the treatment of patients with metastatic breast carcinoma. METHODS: Doxorubicin (50 mg/m2, bolus) followed by paclitaxel (175 mg/m2 over 3 hours) was administered every 21 days (for a maximum of 10 cycles) as first-line chemotherapy in 77 patients, 41 of whom had received prior adjuvant chemotherapy. Monitoring of cardiac function (left ventricular ejection fraction[LVEF]) and total doxorubicin cumulative dose were included in the study protocol. RESULTS: Grade 4 hematologic toxicities were neutropenia (58%) and thrombocytopenia (4%). Neutropenic fever occurred in 9% of patients. Nonhematologic Grade 4 toxicity was limited to mucositis (3%). Grade 3 toxicities were neutropenia (35%), anemia (3%), alopecia (93%), peripheral neuropathy (18%), arthralgia/myalgia (8%), and mucositis (9%). No clinical cardiotoxicity (Grades 3 or 4) occurred. Treatment was discontinued in 5 patients who showed a decrease of LVEF of greater than 15% during therapy. Of 73 patients assessable for response, 15 were complete response, 42 partial response, 15 stable disease, and 1 disease progression; overall response rate being 78% (95% confidence interval [CI], 67-87). Median follow-up was 22 months. Median time to progression (TP) was 10 months (95% CI, 7-12). Time to progression was poorer in cases with adjuvant anthracycline therapy than those without adjuvant chemotherapy (7 vs. 12.3 months; P = 0.022), but TP in patients with adjuvant chemotherapy not containing anthracyclines was not different from the cases without adjuvant chemotherapy (8.6 months). Estimated 2-year survival was 51% (standard error, 7%). CONCLUSIONS: Our results confirm that the combination of paclitaxel and doxorubicin is effective in the treatment of metastatic breast carcinoma, and that it is well tolerated. No clinical cardiotoxicity was observed on close cardiac monitoring, and prior adjuvant anthracycline treatment compromised its efficacy.     

First-line treatment for advanced ovarian cancer: paclitaxel,platinum and the evidence

Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of 'crossover' to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen 'within' and 'between' groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity 'within' and 'between' groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer.     

Corynebacterium parvum toxicity in patients with limited and advanced malignancy

The toxicity of intravenously administered Corynebacterium parvum was observed in 14 patients with stage II melanoma and in 14 patients with advanced ovarian carcinoma. Those with melanoma were rendered disease-free by surgery prior to treatment. The ovarian cancer patients had failed chemotherapy with alkylating agents and were receiving C. parvum prior to chemotherapy as part of an immunochemotherapy trial. Both clinical and laboratory parameters were observed. The mean daily C. parvum dose for melanoma patients was 2.03 mg/m² and for ovarian carcinoma patients 2.02 mg/m². The most important clinical toxic effects noted were fever, chills, blood pressure changes, headache, nausea, vomiting and diaphoresis. Laboratory toxicity was mild, with small decreases in hemoglobin levels, white blood cell counts and uric acid and albumin concentrations occurring in some patients. Serum bilirubin and SGOT levels tended to rise. In addition to determining the frequency of clinical toxic effects by treatment course, consideration was also given to frequency per treatment day, correlation of the occurrence of different toxicities in the same patient, time of onset of each toxicity and, for vital signs, to intensity of change and duration. In this analysis no major differences in toxicity were observed when C. parvum was given to the two patient groups.     

Intensity-modulated radiotherapy combined with paclitaxel and platinum treatment regimens in locally advanced esophageal squamous cell carcinoma

Purpose

This study was conducted to investigate the efficacy and toxicity of combination treatment with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy with paclitaxel plus different platinum agents in locally advanced esophageal squamous cell carcinoma (ESCC).

Methods

This retrospective study enrolled 242 patients treated with paclitaxel (135 mg/m²) plus platinum regimens. According to the different platinum agents used, patients were classified into: cisplatin 80 mg/m² (CP), nidaplatinum 80 mg/m² (NP), lobaplatin 35 mg/m² (LP), and oxaliplatin 135 mg m² (OP) groups, and survival and toxicity rates between the four groups were compared. The median overall survival (OS) was 31.1 months.

Results

No significant differences were observed among the CP, NP, LP, and OP groups with regard to 3-year survival rates (46.2, 56.4, 45.7, and 29.0%, respectively). A stratified analysis indicated that 3-year survival rates were significantly lower in the OP group. Renal toxicities and gastrointestinal reactions were more frequent in the CP group than in the other three groups. Three-year survival rates were similar among patients receiving 2, 3, or ≥4 cycles of chemotherapy (40.1, 49.5, and 50.8%, respectively). Multivariate analysis indicated that tumor volume and maximum diameter of metastatic lymph nodes might be independent prognostic factors.

Conclusion

Paclitaxel plus nidaplatinum or lobaplatin is recommended in locally advanced ESCC due to their satisfying therapeutic effects and less toxicity. Tumor volume and maximum diameter of metastatic lymph nodes are independent prognostic factors in ESCC patients receiving IMRT and concurrent chemotherapy.

     

Palliative urinary diversion in patients with advanced pelvic malignancy

The survival patterns of 90 patients with advanced pelvic malignancy and bilateral ureteral obstruction treated with urinary diversion are reviewed. Cell type, presence or absence of prior treatment, or degree of renal decompensation had no specific correlation with length of survival. The youngest age group ranging from 27 to 49 years had a significantly shorter survival than the remainder of the patients. In patients who received prior treatment, an increasing time interval from original diagnosis of malignancy to diversion was associated with a longer median survival. Thirty patients lived six months or more after surgery and spent an average of 14% of their remaining life in the hospital. Guidelines for selection of patients who might benefit from urinary diversion are presented.     

Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum

Background  

Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum.     

Biweekly paclitaxel and cisplatin in patients with advanced head and neck carcinoma

Background: Cisplatin is an active drug in head and neck cancer. Paclitaxel seems a promising drug. This article reports a phase II assessment of the combination of the two.Patients and methods: Twenty-three patients were treated with paclitaxel 90 mg/m² over three hours plus cisplatin 60 mg/m² every other week. Sixteen patients had locoregional disease and seven had metastatic disease. None of the patients had previously been treated with chemotherapy. Nine patients had had radiotherapy to the target lesions.Results: One patient was not evaluable for response. Partial responses were observed in 32% of evaluable patients. Toxicity included asthenia (56%), neutropenia, peripheral neuropathy, anemia and vomiting.Conclusions: The overall response rate observed in this study does not seem to justify the use of this chemotherapy regimen in the palliative setting.     

Pharmacokinetics of paclitaxel and three major metabolites in patients with advanced breast carcinoma refractory to anthracycline therapy treated with a 3-hour paclitaxel infusion: A European Cancer Centre (ECC) trial

BACKGROUND: Hepatic metabolism and biliary clearance play pivotal rolesin the disposition of the anticancer drug paclitaxel. 6-     

白蛋白结合型紫杉醇联合铂类药物治疗晚期转移性三阴性乳腺癌的临床价值分析

目的 分析白蛋白结合型紫杉醇联合铂类药物治疗晚期转移性三阴性乳腺癌(TNBC)的临床价值.方法 将68例TNBC患者按治疗药物不同分为观察组与对照组,各34例,对照组给予常规化疗药物治疗,观察组给予白蛋白结合型紫杉醇联合铂类药物治疗.比较两组患者治疗后临床疗效、用药期间不良反应发生情况及生存情况.结果 观察组患者客观缓解率高于对照组,差异有统计学意义(P﹤0.05).观察组患者3～4级贫血、恶心、呕吐、白细胞异常、中性粒细胞减少、血小板减少、肝功能异常、肾功能异常、外周神经毒性不良反应发生率均明显低于对照组,差异均有统计学意义(P﹤0.05).观察组患者1年生存率高于对照组,差异有统计学意义(P﹤0.05).结论 白蛋白结合型紫杉醇联合顺铂治疗晚期转移性TNBC临床疗效相对常规化疗方案较好,同时降低各不良反应的严重程度,提高患者化疗耐受力,近期疗效较好.     

紫杉醇联合草酸铂治疗30例晚期胃癌

目的 研究联合紫杉醇及草酸铂两种新药用于治疗晚期胃癌，并评价此方案的近期疗效及其毒副作用。方法：对入选的30例晚期胃癌患者以紫杉醇联合草酸铂(单周或双周)方案予全身化疗，并配合每周1次顺铂(DDP)或氟嘧啶脱氧核苷(FUDR)单药腹腔灌注化疗。结果：30例胃癌患者平均化疗1．2个疗程，CR2例，PR17例，总有效率RR(CR PR百分率)为63％、(95％可信区间为46％～80％)。毒副反应主要为骨髓抑制，发生率达77％，但60％为Ⅰ-Ⅱ度，有3例(10％)为Ⅳ度；胃肠道反应、肝功损害、末梢神经炎、肾功损害、粘膜炎及心脏毒性发生率分别为40％、30％、13％、10％、10％及7％，大都为Ⅰ-Ⅱ度。所有患者均未因毒副作用中断或退出治疗。结论：紫杉醇联合草酸铂方案治疗晚期胃癌近期疗效是肯定的，毒副反应较轻，适合于对其他化疗反应大、有潜在心、肝、肾功不良或年老体弱、多次化疗后、恶性度高或急需减瘤考虑Ⅱ期手术的患者。     

Phase II study of paclitaxel and carboplatin in advanced gastric cancer previously treated with 5-fluorouracil and platinum

BACKGROUND: The combination of paclitaxel and carboplatin has been used to treat patients with many types of tumor, including gastric cancer. We evaluated the efficacy and safety of this combination in advanced gastric cancer patients previously treated with 5-fluorouracil and platinum. METHODS: Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel (200 mg/m(2) for 3 h) and carboplatin [area under the concentration-time curve (AUC = 6)] on day 1 and in 21 day cycles. RESULTS: A partial response was achieved in 10 of 45 patients [22%, 95% confidence interval (CI), 10-34]. Of the 32 patients previously treated with cisplatin, four (13%) achieved partial response, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved partial response. In all patients, the median time to progression was 14 weeks (95% CI, 10-18), and the median overall survival was 32 weeks (95% CI, 26-38). The most common grade 3/4 adverse events were neutropenia (40% of patients) and neuropathy (2.2%). Two patients developed neutropenic fever. However, there were no treatment-related deaths. CONCLUSIONS: Combination chemotherapy with paclitaxel and carboplatin is feasible in patients with advanced gastric cancer who were previously treated with 5-fluorouracil and platinum.     

Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer

PURPOSE: Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors. PATIENTS AND METHODS: A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1. RESULTS: Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P>0.05). CONCLUSIONS: Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.     

Peripheral neuropathy due to therapy with paclitaxel,gemcitabine, and cisplatin in patients with advanced ovarian cancer

Background: To evaluate the peripheral neuropathic changes induced by combination chemotherapy including paclitaxel (taxol), gemcitabine and cisplatin (TGC regimen). Patients and methods: Eighteen patients with primary or recurrent ovarian cancer were treated with paclitaxel 150 or 110mg/m², respectively, together with gemcitabine 800mg/m² and cisplatin 75mg/m², 3 weekly for 6 cycles.Neurologic evaluation and quantitative assessment by vibration perception threshold (VPT) and grip strength took place before therapy, after 3 and 6 cycles of chemotherapy, and thereafter when possible. Results: Both neuropathic symptoms and signs developed in all patients (100%), becoming most prominent 3 months after the last course of chemotherapy. Grade 3 peripheral neuropathy developed in one patient during chemotherapy, and in 3 additional patients after cessation of therapy.No significant differences were observed between chemo-naïve patients and pretreated patients. Conclusion: This TGC combination is well tolerated in terms of peripheral neuropathy during therapy, although the off-therapy worsening caused by cisplatin remains a problem.     

Phase II study of gemcitabine plus paclitaxel in metastatic breast cancer patients with prior anthracycline exposure

Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. Patients and Methods: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m² was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m² was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. Results: Objective response rate was 41.7 percent (95 percent CI: 21.9-61.4) with 16.7 percent (95 percent CI: 1.7-31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6-42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3-4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. Conclusion: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.     

Effects of anthracycline therapy on intestinal absorption in patients with advanced breast cancer

Although cytotoxic chemotherapy for human cancer has been reported to induce alterations in intestinal permeability, its effects on the absorptive process are still controversial. We have studied mediated and nonmediated absorption in 10 patients with metastatic breast cancer before and after treatment with Adriamycin by the use of specific test sugars given orally and their subsequent urinary recovery, as measured by chromatography. Mediated absorption was investigated by the use of D-xylose and 3-O-methylglucose, while lactulose and L-rhamnose were used to study nonmediated permeation. Lactulose is considered a marker of unmediated paracellular (tight junction) permeation, while L-rhamnose explores passage across cell membranes. The test was performed on patients before and on the second and the eighth days after Adriamycin administration, and only once in 22 age-matched healthy women. Under basal conditions, as well as 2 and 8 days after chemotherapy, D-xylose and 3-O-methylglucose absorption was 35% lower in patients than in controls (P less than 0.001). Lactulose absorption was significantly higher in patients than in controls under basal conditions (P less than 0.001); it reached levels three times higher the second day after chemotherapy, and returned to basal levels by the eighth day. The data suggest an early reversible effect of Adriamycin on cellular tight junctions with resulting increased permeabilization. This effect seems of a toxic nature rather than due to increased cell loss. It is interesting that both nonmediated absorption and mediated absorption were already altered before chemotherapy in cancer patients, suggesting a preexisting functional damage of the intestine. The significance of this alteration as a potential mechanism of cancer cachexia is discussed.     

Second-line chemotherapy with weekly paclitaxel in patients with advanced non-small-cell lung cancer

In this phase II study we assessed the activity and toxicity of weekly paclitaxel in second line treatment of non-small-cell lung cancer. Sixteen patients were included. Disease staging was IV in 12 patients and IIIB in 4. Paclitaxel (80 mg/m²) was administered as a weekly 1 hour infusion. Partial response was observed in two patients, stable disease in 4 and progression in 10. The median progression time was 78 days and the median survival was 160 days. There was not severe toxicity. Weekly infusion of paclitaxel as second-line chemotherapy induces moderate rates of response with excellent tolerance.