Pharmacokinetics of an etoposide infused over three days: concomitant infusion with cisplatin.

The pharmacokinetics of a 72-hour infusion of 240 mg/m2 etoposide administered concurrently with 90 mg/m2 cisplatin was studied in 12 lung cancer patients. The area under the curve (AUC), elimination half-life, steady state concentration, systemic clearance, renal clearance of etoposide and distribution volume at steady state were 225.4 +/- 39.2 micrograms x h/ml, 8.1 +/- 3.4 h, 3.1 +/- 0.6 micrograms/ml, 18.8 +/- 3.1 ml/min/m2, 3.1 +/- 1.4 ml/min/m2, 9.6 +/- 3.8 l/m2, respectively, which were in accordance with those reported previously in patients treated with etoposide alone. Although concentration at 24 hours, total bilirubin level and total protein level were correlated with the AUC which in turn correlated with hematologic toxicity, the variables were not predictive of hematologic toxicity. We conclude that the concomitant administration of cisplatin at a dose level of 30 mg/m2/day might not affect the pharmacokinetics of prolonged etoposide infusion.     

Multicenter phase II study of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric cancer

Purpose Since a weekly administration of paclitaxel has demonstrated a sustained efficacy and more favorable toxicity profile than a 3-weekly administration for various solid tumors, the present study was conducted to evaluate the efficacy and safety of a combination regimen of weekly paclitaxel plus cisplatin in patients with advanced gastric cancer. Patients and methods Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous paclitaxel 100 mg/m² plus cisplatin 35 mg/m² on days 1 and 8 based on a 3-week cycle. Results Fifty-two patients were enrolled in the current study. Two complete responses and 17 partial responses were confirmed, giving an overall response rate of 36.5%. At a median follow-up of 8.5 months, the median time to progression and median overall survival was 6.0 and 10.8 months, respectively. Grade 3 neutropenia occurred in ten patients, while no grade 4 neutropenia or febrile neutropenia was observed. The most common non-hematologic toxicity was nausea (grade 1/2, 56.9%). There were no treatment-related deaths. Conclusion A weekly paclitaxel and cisplatin combination was found to be well-tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.     

Phase I study of paclitaxel poliglumex administered weekly for patients with advanced solid malignancies

Background

Paclitaxel poliglumex (PPX, also called Xyotax^® or CT-2103) is a water soluble macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-l-glutamic acid. The recommended phase II dose of PPX every 3 week is 235 mg/m² administered over a 10-min infusion without premedication. This study was designed to determine the MTD and pharmacology of PPX administered weekly to patients with solid malignancies.

Methods

The starting dose of weekly PPX was 20 mg/m². Each cycle consists of 6 weekly treatments with pharmacokinetics of PPX (the conjugated paclitaxel) and unconjugated paclitaxel obtained after the first and sixth dose. Three to six patients were enrolled at each dose level. Toxicity and response were assessed by the NCI Common Toxicity criteria version 2 and RECIST criteria, respectively.

Results

Twenty-six patients were treated with PPX at the following dose levels: 20 mg/m² (five patients), 40 mg/m² (four patients), 60 mg/m² (four patients), 70 mg/m² (eight patients) and 80 mg/m² (five patients). Dose-limiting toxicities, consisting of grade 3 neutropenia, occurred in the 80 mg/m² cohort during cycle 1. Therefore, the dose recommended for phase II studies was 70 mg/m². In this cohort, a single dose-limiting event, consisting of diarrhea, was seen. Neuropathy and fatigue were the most common toxicities. No objective responses were noted. Pharmacokinetics was dose-proportional, and the degree of neutropenia related to drug exposure, but not to peak plasma concentration. There was no significant accumulation of conjugated or unconjugated paclitaxel with this dosing schedule.

Conclusions

The recommended dose of PPX for subsequent disease-directed studies is 70 mg/m² weekly.     

A phase I and pharmacokinetic study of paclitaxel poliglumex and cisplatin in patients with advanced solid tumors

Purpose  Determine the toxicity, maximum tolerated dose (MTD), and pharmacokinetics of paclitaxel poliglumex (PPX; CT-2103) in combination with cisplatin administered every 3 weeks. Patients and methods  Forty-three patients with advanced solid tumors were treated at escalating doses of PPX with a fixed dose of cisplatin at 75 mg/m². Conjugated and unconjugated paclitaxel were measured in plasma and urine. Cisplatin, as total platinum content in urine, was also assayed. Results  Dose-limiting toxicities included neutropenia and neuropathy with a cycle 1 MTD of 210 mg/m². Conjugated taxanes had a prolonged half-life of >100 h. Nine patients had partial responses, and 19 had stable disease. Conclusions  PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and a limited volume of distribution. PPX/cisplatin showed good activity in a refractory patient population; however, cumulative neuropathy was a significant issue at high doses, suggesting that a lower dose may be appropriate for prolonged therapy. The authors who are not employed by Cell Therapeutics do not have disclosure to make.     

Chemotherapy with etoposide,doxorubicin, cisplatin, 5-fluorouracil,and leucovorin for patients with advanced hepatocellular carcinoma

BACKGROUND: To investigate the therapeutic index of combining etoposide, doxorubicin (adriamycin), cisplatin, 5-fluorouracil (5-FU), and leucovorin (EAPFL) chemotherapy in the treatment of advanced HCC, a trial of a novel schedule of triweekly administration was conducted. PATIENTS AND METHODS: Sixty-six patients with measurable advanced HCC, adequate liver and renal functions and adequate bone marrow reserves in whom local treatment was not indicated were studied. Triweekly EAPFL treatment consisted of a concomitant boost of etoposide 40 mg/m2 i.v. over 30 min on day 1, 2, and 3, doxorubicin 30 mg/m2 i.v. over 30 min on day 1 to a backbone regimen, triweekly PFL chemotherapy with cisplatin 60 mg/m2, 5-FU 1,200 mg/m2, and leucovorin 120 mg/m2 given simultaneously by a 72-h i.v. infusion. Response, survival, and toxicity were evaluated. RESULTS: One patient had complete response (1%) and thirteen patients had partial response (20%). The objective response rate was 21% (95% confidence interval 11-31%). The median overall survival and median time to progression were 8.9 months and 3.3 months, respectively. Major treatment toxicities (grade 3-4) were neutropenia (28%), anemia (11%), thrombocytopenia (7%), hepatotoxicity (5%), vomiting (2%), and diarrhea (2%). There was no treatment-related death. CONCLUSION: Triweekly EAPFL chemotherapy is a moderately effective regimen with tolerable toxicities in the treatment of advanced HCC.     

Dose escalation and pharmacokinetic study of irinotecan in combination with paclitaxel in patients with advanced cancer

Purpose: Based on preclinical data demonstrating synergy between camptothecin analogues and taxanes, we determined the maximum tolerated dose (MTD) of irinotecan that could be given in combination with a fixed dose of paclitaxel of 75 mg/m², when both drugs were delivered on a weekly schedule. The pharmacokinetics of this combination were explored to determine whether the sequence of administration affected the elimination of irinotecan. Methods: For the first cycle patients with advanced cancer were treated with irinotecan given as a 90-min infusion followed immediately by paclitaxel given at a dose of 75 mg/m² over 1 h. The sequence of drug administration was reversed in subsequent cycles for most patients. Chemotherapy was given weekly for 4 weeks, followed by a 2-week rest. In selected patients, plasma concentrations of irinotecan were determined by high-performance liquid chromatography during the first 24 h of cycle 1 and after the first dose of cycle 2 to determine whether the order of drug administration affected the elimination of irinotecan, or the toxicologic effects of the chemotherapy. Results: A total of 53 cycles were delivered to 21 patients. Reversible neutropenia was dose-limiting. Suppression of the other blood cell elements was modest. There was one partial response in a man with a previously treated cholangiocarcinoma that lasted 26 weeks. Prolonged stabilization of disease (6 months or more) was observed in five of the patients (24%). At the recommended dose of irinotecan (50 mg/m²), transfusions of red cells and platelets were not required. The sequence of drug administration produced no significant differences in the pharmacokinetic parameters of irinotecan or SN-38, which were similar to the values reported when irinotecan is administered alone. The most prominent nonhematologic toxicities were mild diarrhea and fatigue. Conclusions: The recommended dose of irinotecan on this schedule is 50 mg/m². The sequence of drug administration affects neither the elimination of irinotecan nor the chemotherapy-related toxicity. This combination is well tolerated and causes minimal clinical side effects. Received: 5 July 1999 / Accepted: 3 February 2000     

Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma

Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n= 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17–95%)] and clearance [CL, 1.1 (0.7–2.3) l h⁻¹ m⁻²] resulting in a normal degree of systemic exposure (AUC_oral 27 μg h ml⁻¹). Normal protein binding [PB 93.2% (84.4–98.1%)] contributed to a normal level of exposure to free drug (AUC_{f, oral} 1.9 μg h ml⁻¹). The distribution volume [V_SS 8.4 (6.1–13.2) l/m²] and the effective half-life [t _1/2eff, 5.1 (3.0–9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of >1.2 mg/dl as compared with the ten patients with total bilirubin levels of ≤1.2 mg/dl (1.3 versus 1.0 l h⁻¹ m⁻² and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring. Received: 11 May 1998 / Accepted: 5 August 1998     

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer

Background Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents. Methods Nineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m² dose of CDDP. Results In the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18mg/m², with CDDP 3mg/m², to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16mg/m² with CDDP, 3mg/m². In the phase II part of the study, the response rate was 25.0%; five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%). Conclusion The RD was determined to be TXL 14mg/m², with CDDP 3mg/m².     

NP方案与TP方案治疗晚期非小细胞肺癌临床分析

目的评价NP方案、TP方案治疗晚期非小细胞肺癌的疗效和毒副反应.方法 NP方案:长春瑞滨(NVB) 25 mg/m2,快速静脉滴注,第1、8天;顺铂(PDD)45 mg/m2,静脉点滴,第1～2天.TP方案:紫杉醇(PTX)135 mg/m2,静脉点滴,第1天,持续3 h;PDD 80 mg/m2,静脉点滴,第2天.21 d为一周期.结果 NP组30例,CR 2例(6.7%),PR 12例(40.0%),SD 12例(40.0%),总有效率46.7%;TP组29例,CR 1例(3.4%),PR 12例(41.4%),SD 11例(37.9%),总有效率44.8%.NP组和TP组中位缓解时间分别为5.5个月和4.5个月.初治优于复治(NP组为72.7%对31.6%,P=0.0308;TP组为75.0%对33.3%,P=0.0480);Ⅲb期优于Ⅳ期(NP组为77.8%对33.3%,P=0.0288;TP组为85.7%对31.8%,P=0.0176).剂量限制性毒性主要为骨髓抑制,NP组较TP组稍重,白细胞、血小板减少发生率分别为66.7%、51.7%和33.3%、31.0%.TP组脱发、周围神经毒性/疼痛较NP组重,而NP组静脉炎及胃肠道反应较TP组重.无Ⅳ度反应出现,患者均能够较好地耐受,不影响化疗继续进行.结论 NP方案、TP方案治疗晚期非小细胞肺癌安全有效,既可用作一线方案,也可用作二线方案,且二者无明显交叉耐药性,可互为挽救方案.     

紫杉醇脂质体与紫杉醇联合顺铂治疗晚期非小细胞肺癌对比研究

目的　探讨紫杉醇脂质体与紫杉醇联合顺铂治疗晚期非小细胞肺癌（ＮＳＣＬＣ）的临床疗效及不良反应。方法　晚期ＮＳＣＬＣ患者７２例,随机分为试验组与对照组,试验组采用紫杉醇脂质体１３５ｍｇ／ｍ^２,对照组采用紫杉醇１３５ｍｇ／ｍ^２化疗,两组均联合顺铂,２１天为１个周期,治疗２个周期后评价疗效。记录近期疗效与治疗期间毒副反应。结果　试验组有效率为４１.７％（１５／３６）,临床受益率为７７.７％（２８／３６）,对照组有效率为３８.９％（１４／３６）,临床受益率为７２.２％（２６／３６）,两组差异均无统计学意义（Ｐ＞０.０５）。白细胞减少和血小板减少的发生率两组差异无统计学意义（Ｐ＞０.０５）,脱发、腹泻、便秘及呼吸困难的发生率两组差异亦无统计学意义（Ｐ＞０.０５）,但试验组恶心、呕吐、皮疹、肌肉痛的发生率明显低于对照组（Ｐ＜０.０５）。结论　紫杉醇脂质体联合顺铂治疗晚期ＮＳＣＬＣ近期疗效确切有效,毒副反应较紫杉醇联合顺铂化疗为轻。     

Comparison of concurrent chemoradiotherapy with cisplatin plus 5-fluorouracil versus cisplatin plus paclitaxel in patients with locally advanced cervical carcinoma

Objective

The aim of this study was to compare survival outcomes and toxicities between concurrent radiotherapy with cisplatin plus 5-fluorouracil and that with cisplatin plus paclitaxel in patients with locally advanced cervical carcinoma.

Methods

We retrospectively reviewed data from 93 locally advanced cervical carcinoma patients (stage IB to IVA) who had been treated by concurrent radiotherapy with cisplatin plus 5-fluorouracil (CF, n=45) vs. cisplatin plus paclitaxel (CP, n=48) as primary therapy. Toxicities and survival outcomes were compared.

Results

In the CP group, there were higher frequencies of severe (grade 3 or 4) leukopenia (79.2%, as compared to 11.1% in the CF group), severe neutropenia (77.1%, as compared to 8.9% in the CF group) and severe peripheral neuropathy (12.5%, as compared to 2.2% in the CF group). In the CF group, there were higher frequencies of severe nausea (33.3%, as compared to 14.6% in the CP group) and severe hyponatremia (11.1%, as compared to 0% in the CP group). Five-year DFS of the CF and CP groups was 67.4% and 79.1%, respectively (p=NS). Five year OS of the CF and CP groups was 79.6% and 80.9%, respectively (p=NS).

Conclusion

Concurrent radiotherapy with cisplatin plus paclitaxel showed increased leukopenia, neutropenia and peripheral neuropathy, but less gastrointestinal toxicity (nausea) than that with cisplatin plus 5-fluorouracil. Survival outcome between these two groups was not statistically different in this study. Large prospective randomized controlled studies will be needed to confirm this result.     

紫杉醇联合顺铂治疗晚期食管鳞癌

目的研究紫杉醇联合顺铂治疗晚期食管癌的疗效和毒副反应。方法30例晚期食管磷癌患者中,27例为初次化疗患者,3例患者曾接受术后辅助化疗。中位年龄58岁。紫杉醇175mg／m^2,d1,静脉滴注3h;顺铂40mg/m^2,d2,d3;21d为1个周期。结果30例患者共完成89个化疗周期。在可评价疗效的27例患者中,完全缓解5例(18．5％),部分缓解11例(40．7％),有效率为59．3％。中位疾病进展时间为5．0个月,中位生存时间9．7个月。可评价毒副反应28例,其主要的毒副反应为脱发,有5例(17．9％)患者出现Ⅲ-Ⅳ度中性粒细胞降低。结论紫杉醇联合顺铂对晚期食管癌疗效肯定,可以考虑作为治疗晚期食管癌的主要治疗方案。     

紫杉醇、卡铂方案与异环磷酰胺、鬼臼乙叉甙、卡铂方案治疗晚期非小细胞肺癌的比较

背景及目的:以铂类为基础的联合化疗已证实对晚期非小细胞肺癌(non-smallcelllungcancer,NSCLC)患者有益。含卡铂的联合化疗方案与含顺铂者相比,前者虽然有效率稍低,但生存期较长、毒性较低。对于姑息治疗而言,较低的毒性及较长的生存期比有效率更有意义,因此我们选择了以卡铂为基础的联合化疗方案犤紫杉醇、卡铂(PC)与异环磷酰胺、鬼臼乙叉甙、卡铂(IEC)犦治疗晚期NSCLC,并比较这两种方案的疗效和毒性。方法:68例晚期NSCLC患者分别接受PC与IEC化疗,PC方案35例,IEC方案33例。两组病人特征具有可比性(P>0.05)。结果:PC组PR14例,NC19例,PD2例,有效率为40.0%(14/35,95%可信区间犤CI犦:23.8%-56.2%),中位生存期9.1个月(95%CI:7.2-11.0个月),1年生存率为25.7%(95%CI:11.2%-40.2%);IEC组PR7例,NC24例,PD2例,有效率为21.2%(7/33,95%CI:7.3%-35.1%),中位生存期7.8个月(95%CI:6.2-9.4个月),1年生存率为20.0%(95%CI:6.0%-34.0%)。PC组的有效率、中位生存期及1年生存率均优于IEC组,但均无统计学差异(有效率:P=0.094,χ2检验;生存期P=0.684,Log-rank检验)。PC组血液学毒性较IEC组低,其中两组白细胞减少(P<0.0005,秩和检验)及血红蛋白减少(P=0.006,秩和检验)差异有统计学意义;血尿及药物热IEC组较高,过敏反应则PC组较     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

周剂量紫杉醇联合顺铂治疗晚期食管癌的临床观察

目的:观察分析周剂量紫杉醇(PTX)联合顺铂(DDP)方案治疗晚期食管癌的近期疗效和毒副反应。方法:29例Ⅲ、Ⅳ晚期食管癌患者,给予周剂量PTX DDP,即PTX80mg/m2d1、d8,DDP40mgd1～d3,21d为1周期,2周期后按WHO标准评价疗效和毒副反应。结果:全组29例,均可评价疗效,总有效率55.2%,16例初治组有效率为62.5%,13例复治组有效率为46.2%。不良反应主要表现为白细胞减少、胃肠道反应和脱发。结论:周剂量紫杉醇联合顺铂治疗晚期食管癌的近期疗效较高,毒副反应轻,值得进一步观察应用。     

Phase I study of etoposide, cisplatin and irinotecan triplet in patients with advanced-stage small-cell lung cancer

Aim The irinotecan–cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan.Methods Successive cohorts of AS-SCLC patients were treated with irinotecan administered as a single 1-h infusion in combination with fixed doses of cisplatin (20 mg/m²) and etoposide (75 mg/m²), both given for three consecutive days (ECI regimen). Irinotecan dose was escalated from 60 mg/m² by 40-mg/m² increments. At mid-step between the maximum tolerated dose (MTD) and the previous dose level, patients were randomized for the day of administration of irinotecan (day 1 vs day 3).Results A total of 36 AS-SCLC patients received 166 courses of treatment at four dose levels. The MTD of irinotecan was 140 mg/m² (three dose-limiting toxicities, DLTs), and the recommended optimal dose (ROD) 120 mg/m² (two DLTs). DLTs were febrile neutropenia and grade 3 diarrhea. Other toxicities were mild. No difference in toxicity was seen between the two time schedules. A 77% (95% CI 63.25–90.75%) response rate was recorded among 31 evaluable patients and the median survival was 12 months.Conclusions The ECI regimen was well tolerated and showed considerable activity in patients with AS-SCLC. Phase II/III evaluation is ongoing.The results of this trial were presented at ECCO 12, Copenhagen, Denmark, September 2003.     

Novel paclitaxel formulations for oral application: a phase I pharmacokinetic study in patients with solid tumours

Purpose To explore the pharmacokinetics (PKs) of paclitaxel and two major metabolites after three single oral administrations of a novel drinking solution and two capsule formulations in combination with cyclosporin A (CsA) in patients with advanced cancer. Moreover, the tolerability and safety of the formulations was studied. In addition, single nucleotide polymorphisms in the multidrug resistance (MDR1) gene were determined. Patients and methods Ten patients were enrolled and randomized to receive CsA 10 mg/kg followed by oral paclitaxel 180 mg given as (1) drinking solution (formulation 1), (2) capsule formulation 2B, and (3) capsule formulation 2C on day 1, 8, or 15. Results The median C _max of paclitaxel was 0.42 (0.23–0.96), 0.48 (0.08–0.59), and 0.39 (0.11–1.03) μg/ml and the area under the plasma concentration–time curve was 2.83 (1.69–5.12), 2.01 (1.57–3.04), and 2.67 (1.05–3.61) μg h/ml following administration of formulations 1, 2B, and 2C, respectively. The novel formulations were tolerated after single oral dose without causing relevant gastrointestinal or haematological toxicity. Conclusions The PK and metabolism of paclitaxel were comparable between the oral formulations co-administered with CsA.     

紫杉醇、顺铂和替吉奥联合化疗方案治疗晚期胃癌的疗效和安全性

目的:探讨紫杉醇联合顺铂(腹腔给药)和替吉奥(TS-1)治疗晚期胃癌的疗效和安全性.方法:连续收集2008年1月-2011年1月接受住院治疗的50例晚期胃癌患者.采用紫杉醇(静脉给药)联合顺铂(腹腔给药)和TS-1(口服给药)方案进行治疗,评价近期疗效和不良反应.平均随访时间为11.4个月,计算无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS).结果:50例患者中,完全缓解5例,部分缓解23例,客观缓解率为56％.中位PFS为6.0个月(95％可信区间:3.4～8.6个月),中位OS为13.0个月(95％可信区间:7.9～18.1个月).主要不良反应为胃肠系统不良反应、血液学毒性和疲乏,多为Ⅰ～Ⅱ度;有3例患者发生Ⅲ～Ⅳ度不良反应(1例为呕吐,2例为肝功能损害).2例在化疗前存在不完全性肠梗阻的患者,接受化疗2个周期后肠梗阻缓解;另1例患者在腹腔化疗后发生化疗相关性肠梗阻.结论:紫杉醇联合顺铂和TS-1治疗晚期胃癌的近期和远期疗效均较好,患者耐受良好.     

Actinomycin D,cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia

BackgroundPatients with high-risk gestational trophoblastic neoplasia (GTN) need multi-agent chemotherapy to be cured. The most common regimen is etoposide (E), methotrexate (M) and actinomycin D (A), alternating weekly with cyclophosphamide (C) plus vincristine (O) (EMA/CO). Cisplatin (P) is a very active drug, but it is usually restricted to second-line therapies. Herein, we report the results of a cisplatin-based therapy: APE (actinomycin D, cisplatin, and etoposide).Patients and methodsThe efficacy and safety of APE for high-risk GTN (defined by Institut Gustave-Roussy (IGR) criteria and/or an International Federation of Gynaecology and Obstetrics (FIGO) score >6) are reported. Patients with brain metastasis or placental-site trophoblastic tumour were excluded.ResultsBetween 1985 and 2013, 95 patients were treated with APE for high-risk GTN: 59 patients as first-line, 36 as ⩾2nd-line therapy. There was 94.7% complete remission, though five patients relapsed. One patient died from GTN after multiple lines of chemotherapy. The five-year overall survival rate (median follow-up 5.7 years) was 97% (95% confidence interval (CI): 91–99%). No death from toxicity occurred. Long-term, six grade-1 neuro-toxicities, three grade-1 and two grade-2 oto-toxicities, and one grade-1 renal toxicity were recorded. One patient developed AML-M4 after APE and EMA/CO. Thirty-four of 35 women, who wished to become pregnant, succeeded and all had at least one live birth.ConclusionWith a 97% long-term overall survival rate, limited long-term toxicity, and an excellent reproductive outcome, APE could be regarded as an alternative option to EMA/CO as a standard therapy for high-risk GTN.     

Rotational intraperitoneal pressurized aerosol chemotherapy with paclitaxel and cisplatin: pharmacokinetics,tissue concentrations,and toxicities in a pig model

ObjectiveWe used paclitaxel and cisplatin, known to be effective in intraperitoneal chemotherapy, in a novel prototype of rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) and evaluated the pharmacokinetics, tissue concentrations, and toxicities in a pig model.MethodsWe developed RIPAC, including the nozzle with the conical pendulum motion, and used 10% of intravenous doses of paclitaxel and cisplatin. We used high-performance liquid chromatography followed by tandem mass spectrometry to analyze serum and tissue concentrations. We applied a non-compartment model to study pharmacokinetics to analyze the time-dependent serum concentrations measured before RIPAC to 48 hours. We evaluated the difference in tissue concentrations between twelve peritoneal regions by the modified peritoneal cancer index. For evaluating toxicities, we observed hepatic and renal function until 4 days after RIPAC.ResultsSix pigs underwent RIPAC using paclitaxel (n=3) and cisplatin (n=3). The peak serum concentration (C_max) and the area under the curve were higher for cisplatin, while the time to the peak serum concentration (T_max) was longer for paclitaxel. Moreover, the parietal peritoneum showed higher tissue concentrations than the visceral peritoneum, and the ratio of tissue to serum concentrations using C_max was higher for paclitaxel (172.2–6,237.9) than for cisplatin (0.1–9.3). However, there were no renal and hepatic toxicities after RIPAC with paclitaxel or cisplatin.ConclusionDelayed absorption of paclitaxel sprayed by RIPAC into the peritoneum to the bloodstream may lead to higher tissue concentrations at different regions and lower serum concentrations than cisplatin.