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.     

Synergistic interaction between vinorelbine and gamma-linolenic acid in breast cancer cells

It has been suggested that exogenous unsaturated fatty acids (UFAs) may increase the cytotoxic activity of cancer chemotherapeutic agents. We examined how γ-linolenic acid (GLA; 18 : 3n-6), the most promising UFA in the treatment of human tumors, affects the effectiveness of the lipophilic drug vinorelbine (VNR) on human breast carcinoma cell lines. Cells were exposed simultaneously to VNR and GLA or sequentially to GLA followed by VNR. Cell viability was determined by MTT assay. The increase in VNR-induced cell growth inhibition was measured by dividing the IC₅₀ and IC₇₀ values (50 and 70% inhibitory concentrations, respectively) that were obtained when the cells were exposed to VNR alone with those with VNR plus GLA. We found that GLA enhanced in a dose-dependent manner the cell growth inhibitory activity of VNR on MCF-7 cells (up to 9-fold). As GLA by itself showed anti-proliferative effects, possible GLA-VNR interactions at the cellular level were assessed employing the isobologram analysis and the combination index (CI) method of Chou–Talalay. Both methods showed an overall synergism between GLA and VNR in MCF-7 cells. At a high level of cell kill, the synergism was greater when a 24 h GLA pre-exposure or co-exposures were tested. Synergy was likewise observed with the GLA-VNR combination in MDA-MB-231, T47D, and SK-Br3 breast cancer cells. In all cell lines, the synergism was independent of the treatment schedule and the exposure time. Under conditions inhibiting lipid peroxidation using Vitamin E (dl-α-tocopherol), the enhancing effect of GLA (an easily oxidizable UFA) on VNR activity was partially abolished. However, when Vitamin E was used in combination, a similar synergistic increase in growth inhibition was obtained. These latter observations strongly implies that the synergistic effects of GLA with VNR are not mediated through a mechanism involving a generation of lipoperoxides. For comparison, the effects of other UFAs were examined on VNR chemosensitivity: GLA was the most potent at enhancing VNR activity, followed by docosahexaenoic acid (22 : 6n-3), eicosapentaenoic acid (20 : 5n-3) and α-linolenic acid (18 : 3n-3), whereas linoleic acid (18 : 2n-6) and arachidonic acid (20 : 4n-6) did not increase VNR chemosensitivity. Very high concentrations of oleic acid (OA; 18 : 1n-9), an UFA inversely correlated with breast cancer risk, also enhanced VNR effectiveness. Thus, various types of UFAs were not equivalent with respect to their actions on VNR effectiveness. In conclusion, our results give experimental support to the hypothesis that some UFAs can be used as modulators of tumor cell chemosensitivity and provide the rationale for in vivo preclinical investigation.     

TP和NP方案治疗转移性乳腺癌临床分析

目的评价长春瑞滨联合顺铂(NP方案)及紫杉醇联合顺铂(TP方案)治疗转移性乳腺癌的近期疗效和毒副反应。方法26例晚期乳腺癌患者采用紫杉醇135 mg/m2静脉滴注第1 d,顺铂30 mg/m2静脉滴注第1~3 d联合方案;28例晚期乳腺癌患者采用长春瑞滨25 mg/m2静脉滴注第1 d、第8 d,顺铂用法同TP方案。同时水化、利尿,21~28 d为1周期,两周期后评价疗效。结果TP治疗组CR+PR为69.2%,NP治疗组CR+PR为64.3%,两组疗效比较无显著差别(P>0.05)。毒副反应评价两组主要为骨髓抑制、恶心呕吐、脱发及肌肉关节疼痛,其中TP组肌肉关节疼痛和脱发发生率高于NP组(P<0.05),周围静脉炎NP组高于TP组(P<0.05)。结论NP方案或TP方案对转移性乳腺癌均有较高疗效,毒副反应均可耐受。     

重酒石酸长春瑞滨联合5-氟尿嘧啶治疗胃癌的临床疗效观察

目的探讨重酒石酸长春瑞滨联合5-氟尿嘧啶治疗胃癌的临床疗效。方法33例中晚期胃(贲门)癌患者均经胃镜、病理组织学诊断明确,重酒石酸长春瑞滨+5-氟尿嘧啶组17例(治疗组),丝裂霉素+5-氟尿嘧啶组16例(对照组),均完成1个疗程化疗,两组共配合相同辅助治疗。结果治疗组有效率为35.3%(6/17),对照组有效率为25.0%(4/16),两组差异无显著性(P>0.05)。两组不良反应相比较,骨髓抑制和浅静脉炎发生率差异无显著性(P>0.05),胃肠道反应差异有显著性(P<0.05)。结论重酒石酸长春瑞滨+5-氟尿嘧啶治疗胃癌疗效与丝裂霉素+5-氟尿嘧啶治疗胃癌疗效无显著性差异,治疗过程中患者胃肠道反应有明显差异,丝裂霉素+5-氟尿嘧啶治疗胃癌胃肠道反应较重,恶心、呕吐明显,患者不能耐受;重酒石酸长春瑞滨+5-氟尿嘧啶,患者胃肠道反应较轻,耐受性较好,临床可用于胃肠道肿瘤化疗。     

NP与MVP方案对复治的晚期非小细胞肺癌近期疗效

目的：评价含顺铂的联合方案NP与MVP对复治的晚期非小细胞肺癌的近期疗效。方法：106例晚期非小细胞肺癌随机被分为两组。NP组48例，其中Ⅲb期12例，Ⅳ期26例，鳞癌12例，腺癌30例，鳞腺混合型6例，采用诺维本25mg/m^2静脉推注，第1，8天；顺铂90mg/m^2静脉滴注，第1天（配合水化）。MVP组58例，其中Ⅲb期8例，Ⅳ期50例，鳞癌14例，腺癌36例，鳞腺混合型8例，采用丝裂霉素6mg/m^2静脉推注，第1天；VDS 3mg/m^2静脉推注，第1，8天；顺铂90mg/m^2,静脉滴注，第1天（配合水化）。两方案均为每3周为1周期，治疗2周期后评价疗效与毒副反应。结果：NP组有效率（RR）为37．5％，MVP组RR为31．0％，差异无显著性（P＞0．05）。腺癌疗效比鳞癌稍好，主要毒副反应为骨髓抑制、消化道反应、周围神经毒性及静脉炎。目前均能采取相应的防治措施。结论：NP与MVP方案均为治疗非小细胞肺癌的第一线治疗方案，也适用于复治的晚期非小细胞肺癌，更适用于基层医院的治疗。     

Intravenous Cereport (RMP-7) Enhances Delivery of Hydrophilic Chemotherapeutics and Increases Survival in Rats with Metastatic Tumors in the Brain

Purpose. The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. Methods. Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the hydrophilic (carboplatin) chemotherapeutic agents, as well as the large hydrophilic marker, 70 kDa dextran. Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorelbine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone. Results. Cereport enhanced the uptake of carboplatin and dextran, but not paclitaxel or carmustine. The pattern of Cereport's uptake effect with carboplatin revealed that Cereport selectively increased the proportion of highly permeable regions. Survival was significantly enhanced when Cereport was combined with either carboplatin, vinorelbine, or gemcitabine, but not carmustine, compared to each chemotherapeutic agent alone. Conclusions. These data provide the first evidence that Cereport, or any receptor-mediated approach intended to enhance the permeability of the blood-brain tumor barrier, can increase the delivery hydrophilic drugs to metastatic tumors in the brain, increasing survival in tumor-bearing rats.     

Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study

Purpose:Gemcitabine (GEM) and vinorelbine (VNR) are both activeagainst advanced breast cancer (ABC), being able to induce a median ORR of25% and 40%, respectively. Because of their different mechanismof action and good tolerability, the combination of GEM and VNR has beentested in ABC. Patients and methods:Twenty-nine ABC patients pretreated withanthracycline-taxane were treated with GEM 1000 mg/m² on day 1, 8,15, and VNR 25 mg/m² on day 1 and 8 every twenty-eight days.Analysis of toxicity pattern, response rate, TTP and OS were carried out. Results:Twenty-nine patients were enrolled into the trial. TheORR was 48% (95% CI: 29–67): a CR was observed in threepatients (10%; 95% CI: 2–27), while eleven patients(38%; 95 CI: 21–58) achieved PR, eight (28%) had a SD, andseven (24%) progressed. Toxicity was mainly hematological and included:grade 3 leukopenia in 48% of cases without episodes of neutropenicfever, grade 3–4 thrombocytopenia in 10%, and grade 2 anemia in7%. Non-hematological toxicities were mild and rather infrequent. Conclusions:The GEM–VNR combination seems to be active inpretreated ABC with an acceptable toxicity pattern, and may well reppresentan interesting therapeutic choice after anthracycline/taxane regimens.     

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.     

Dramatic response of choroidal metastases from breast cancer to a combination of trastuzumab and vinorelbine

We report the case of a 57-year-old woman with unilateral choroidal metastases from HER-2-positive breast cancer. She was given trastuzumab and vinorelbine with complete resolution of her visual defect after one cycle of treatment. This article illustrates that treatment using trastuzumab-containing chemotherapy regimens in HER-2-overexpressing breast cancer patients with choroidal metastases may be an alternative therapeutic strategy to initial orbital irradiation.