Emerging therapeutic options for breast cancer chemotherapy during pregnancy.

BACKGROUND: Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting. PATIENTS AND METHODS: We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients. RESULTS: Twenty-four pregnancies are described, in which no grade 3-4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases. CONCLUSION: The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy.     

Effective oral chemotherapy for breast cancer: pillars of strength.

Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. We discuss the benefits and challenges of oral chemotherapy from the perspectives of patients, healthcare providers and healthcare funders. Important issues include patient preference, efficacy, compliance, bioavailability, reimbursement, use in special patient populations, financial and staff time savings and flexibility of dosing. We review data for traditional oral agents (e.g. cyclophosphamide, methotrexate), newer oral chemotherapies (e.g. capecitabine), oral formulations of traditionally intravenous agents (e.g. vinorelbine, idarubicin) and new biologic agents under evaluation in breast cancer (e.g. tyrosine kinase inhibitors). Lastly, we review studies of all-oral combination regimens. The wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings.     

泽菲联合盖诺治疗不能耐受顺铂晚期非小细胞肺癌临床观察

[目的]评价泽菲联合盖诺治疗不能耐受顺铂的晚期非小细胞肺癌的疗效和毒性。[方法]108例Ⅲ和Ⅳ期非小细胞肺癌既往均未曾放疗或化疗,ECOG评分≤2,生存期超过3个月,WBC计数>4.0×109/L,肝、肾功能生化指标正常,未有活动性感染征象。36例以泽菲联合盖诺(GN)为一线方案,另外36例以吉西他滨加顺铂(GP),还有36例以长春瑞滨加顺铂(NP)为一线方案作对照组。[结果]GP组、NP组和GN组RR分别为44.44%、43.24%和33.33%,三组疗效无统计学差异(P>0.05)。GN组与另两组在Ⅲ～Ⅳ度血液学毒性方面比较无统计学差异(P>0.05);GN组非血液学毒性比较少(P<0.01)。[结论]GN方案疗效较好,毒性较低,尤其适合于不能耐受顺铂的晚期NSCLC患者。     

放疗联合长春瑞滨加顺铂同步或序贯化疗治疗Ⅲ期非小细胞肺癌的临床研究

为了比较放射治疗联合长春瑞滨（NVB）加顺铂（DDP）同步与序贯放化疗治疗Ⅲ期非小细胞肺癌（non-small cell lung cancer,NSCLC）的疗效及毒副反应,将55例Ⅲ期NSCLC患者随机分成2组,同步放化疗组（26例）：放疗第1天起即同时开始化疗。序贯放化疗组（29例）：入组后先予化疗2个疗程,再单独予放疗。结果：近期有效率（CR＋PR）同步放化疗组为76.9%（20/26）,序贯放化疗组为51.7%（15/29）,P=0.0456。1、2年生存率同步放化疗组为69.2%（18/26）、42.3%（11/26）,序贯放化疗组为51.7%（15/29）、17.2%（5/29）。2年生存率差异有统计学意义,P=0.041。同步放化疗组白细胞下降与放射性食管炎较序贯放化疗组严重,P〈0.05;但经治疗后,患者大多能耐受。初步研究结果提示,放射治疗联合NVB加DDP同步放化疗治疗Ⅲ期NSCLC的疗效优于序贯放化疗,不良反应增大但可耐受,值得进一步研究。     

Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101).

BACKGROUND: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations. PATIENTS AND METHODS: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m(2) and VNR 25 mg/m(2) on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m(2) and PTX 125 mg/m(2) on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m(2) on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m(2) on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles. RESULTS: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens. CONCLUSIONS: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.     

长春氟宁抗肿瘤作用的研究

目的检测长春氟宁对微管聚集的作用,并研究长春氟宁体外和体内的抗肿瘤作用。方法用浊度实验检测长春氟宁对微管聚集的抑制作用,并以多株肿瘤细胞和荷瘤小鼠分别研究长春氟宁体外、体内的抗肿瘤作用。结果长春氟宁抑制猪脑中提取的微管的聚集,IC50为2.0μmol·L-1;体外试验,长春氟宁抑制多株瘤细胞的IC50在0.05～2.2μmol·L-1之间;体内试验,长春氟宁剂量依赖性地抑制小鼠不同类型移植肿瘤的生长。长春氟宁体外和体内的药物作用比阳性对照药物长春瑞宾弱,但从最大药物疗效来看,长春氟宁对体内肿瘤生长的抑制率比长春瑞宾大。结论长春氟宁能够抑制微管的聚集,在体外体内均有明显的抗肿瘤作用。     

化疗药物对乳腺癌患者糖代谢的影响

目的:探讨化疗药物对乳腺癌患者糖代谢的影响。方法:选择250例女性乳腺癌患者,术后采用紫杉类为主化疗的患者156例,采用长春瑞滨为主化疗的患者94例。对2组化疗前后的血糖水平及相关临床资料进行回顾性分析。结果:250例化疗前空腹血糖均正常,化疗前与6个周期化疗后空腹血糖相比差异有统计学意义(P<0.05)。化疗后空腹血糖升高42例(16.8%),其中明确诊断糖尿病9例,占同期化疗者的3.6%(9/250)。以紫杉类为主化疗的患者156例,发生血糖异常25例(16.03%),占同期化疗者的10.00%(25/250);以长春瑞滨为主化疗的患者94例,发生血糖异常17例(18.09%),占同期化疗者的6.80%(17/250)。在确诊为糖尿病的9例患者中接受以紫杉类为主化疗方案者6例,糖尿病的发生率为3.85%(6/156),以长春瑞滨为主化疗方案者3例,糖尿病的发生率为3.19%(3/94),差异无统计学意义(P>0.05)。2组患者空腹血糖均值随化疗周期变化差异无统计学意义(P>0.05)。结论:乳腺癌患者接受化疗可以引起血糖升高,甚至发生糖尿病,以紫杉类为主的化疗方案与以长春瑞滨为主的化疗方案对患者血糖无明显影响。     

铂类为基础的三种化疗方案治疗晚期非小细胞肺癌的临床研究

目的：观察紫杉醇（paclitaxel，Taxel）、长春瑞滨（vinorelbine，NVB）、吉西他滨（gemcitabine，GEM）分别联合顺铂（cisplatin，DDP）方案对晚期非小细胞肺癌（non—small cell lung cancer，NSCLC）的疗效及毒副反应。方法：93例晚期非小细胞肺癌患者随机分为TP组（紫杉醇＋顺铂）32例、NP组（长春瑞滨＋顺铂）31例、GP组（吉西他滨＋顺铂）30例。给药方法：紫杉醇135mg／m^2，第1天；长春瑞滨25mg／m^2，吉西他滨1000mg／m^2，均在第1、8天使用；顺铂80mg／m^2，分2天使用。统计各组有效率（CR＋PR）、中位生存期（median duration of survival）、1年生存率（1year survival rate）。结果：TP组有效率（CR＋PR）为43．8％，中位生存期为8．6月，1年生存率为32．1％；NP组有效率为38．7％，中位生存期为8．4月，1年生存率为26．5％；GP组有效率为36．7％，中位生存期为9．4月，1年生存率为38．1％，三组间疗效无显著差异（P〉0．05）。主要不良反应为骨髓抑制、消化道反应，均可耐受。11P组骨髓抑制发生率相对较高，NP组静脉炎发生率高于TP、GP组，有显著性差异（P〈0．05）。结论：三种联合化疗方案对晚期NSCLC疗效确切，三种方案间无显著差异，均可作为一线化疗方案在临床应用。     

Mitoxantrone plus vinorelbine with granulocyte-colony stimulating factor (G-CSF) support in advanced breast cancer patients. A dose and schedule finding study

Summary Mitoxantrone (MTZ) and vinorelbine (VNR) have shown a good efficacy in advanced breast cancer. We conducted a phase I-II trial to determine the MTDs and best schedule of these drugs, in advanced breast cancer patients, when granulocyte-colony stimulating factor (G-CSF) support was given. The starting dose-intensity level was MTZ 3 mg/m²/week + VNR 15 mg/m²/week; dose was escalated at each step by 1 mg/m²/week for MTZ and 5 mg/m²/week for VNR, until dose limiting toxicity (DLT) developed in 33% or more of the patients at the first course. G-CSF 5 µg/kg/day d 3–13 was administered at each cycle from dose level 2 on. For each dose step we planned 3 different schedules (a = total dose of MTZ on day 1; b = total dose d 1 and 8; c = weekly schedule). At the time of this analysis (December 1993) 43 patients with locoregionally advanced or metastatic breast cancer have entered this study, 23 of whom had received prior chemotherapy other than adjuvant. Toxicity has been primarily hematologic. Non hematologic toxicity never caused interruption of dose escalation.Overall 8 patients developed DLT at the first course. Dose escalation was stopped at level 3 in patients receiving schedules a or b, and in those receiving schedule c the dose was escalated until level 5. The MTD was MTZ 6 mg/m² and VNR 30 mg/m² weekly. Age, dose level, and PS were found to be correlated with neutrophil and platelet nadirs, but dose level was the only independent variable predictive of myelotoxicity at multiple regression analysis.Forty-one patients were evaluable for response. Five complete and 16 partial responses were recorded for a 51% [35–67] overall response rate. This was 67% (12/18) in chemotherapy naive patients as compared to 39% (9/23) in those who had been pretreated.Seven of 21 (33%) patients receiving dose level 1 and 2 responded as compared to 14/20 (70%) patients who received higher dose-intensity (p = 0.02). Dose level and pretreatment were the only variables significantly associated with response rate at multiple logistic analysis.The median TTP was 9.5 months for the entire group. It was significantly better in patients who received a dose level > 2 (15 vs. 7; p = 0.015). However, the chemotherapy dose level did not significantly predict outcome after correction for pretreatment (yes vs. no), at multivariate Cox analysis.In conclusion, G-CSF support allows us to achieve a high dose-intensity of MTZ and VNR. Weekly administration of mitoxantrone is recommended to achieve the maximum dose level.Dose escalation seems to provide a significant gain in terms of response rate, although the low number of patients enrolled and the short follow-up prevents us from drawing any conclusion on its effects on TTP and survival. Further controlled trials of this combination in unpretreated patients with advanced breast cancer are needed to determine whether dose escalation can really improve prognosis.     

Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials

AIMS: a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters. METHODS: All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20-45 mg m-2. The population pharmacokinetic model was built in a sequential manner on a subset of two-thirds of the data, starting with a covariate-free model then progressing to a covariate model using the nonlinear-mixed effect methodology. The remaining one-third of the data were used to validate several sparse sampling designs. RESULTS: A linear three-compartment model characterized vinorelbine blood concentrations (n=1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CLtotal (l h-1)=29.2xBSAx(1-0.0090 Plt)+6.7xWt/Crs) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Crs) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration. CONCLUSIONS: A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.