Phase I dose finding study evaluating the combination of bendamustine with weekly paclitaxel in patients with pre-treated metastatic breast cancer: RiTa trial

Purpose  The aim of the RiTa trial is to establish a feasible combination of bendamustine and paclitaxel in a weekly schedule in anthracycline pre-treated metastatic breast cancer patients. Methods  Starting dose of bendamustine was 50 mg/m2 and was stepwise increased by 10 mg/m2 up to 70 mg/m2. The starting dose of paclitaxel was 60 mg/m2 and was increased up to 90 mg/m2. There are five pre-defined dose levels with three patients per dose level (maximum six patients) and six patients in the last dose level according to the Goodman design. Dose-limiting toxicities were defined as severe neutropenia and thrombocytopenia as well as non-haematological toxicities ≥NCI-CTC grade 3 in the first cycle. Results  No dose-limiting toxicity up to 70 mg/m2 bendamustine and 90 mg/m² paclitaxel occurred during the first cycle. Over all cycles, the following severe haematological toxicities (grade 3 and 4) were documented: neutropenia five patients and anaemia one patient. Relevant grade 3 and 4 non-haematological toxicities over all cycles were fatigue two patients, dyspnoea one patient, infection four patients and bone pain in one patient. Five serious adverse events, but no therapy related death occurred. Five patients showed a complete or partial remission, six patients stable disease and six progressed during treatment. The median progression-free survival was 8 months. Conclusion  Treatment with weekly bendamustine and paclitaxel is a feasible and effective regimen in patients with metastatic breast cancer. The recommended dose for forthcoming phase II study is 70 mg/m² bendamustine and 90 mg/m² paclitaxel. In part presented at the congress of the German Cancer Society on February 2008 in Berlin.     

Semisolid formulations containing dimethyl sulfoxide and α-tocopherol for the treatment of extravasation of antiblastic agents

The topical treatment with dimethyl sulfoxide (DMSO) and/or α-tocopherol (α-T) is widely used in order to prevent the local complications of extravasation of cytostatic drugs and protect patients against skin ulceration. Till now, DMSO and α-T have been mainly used in solution. The goal of this study was to formulate semisolid preparations for cutaneous application differing in the hydrophilic and lipophilic properties and containing DMSO and α-T in combination. With respect to solutions, the use of semisolid preparations containing DMSO and α-T could be advantageous in patients having extravasation as DMSO and α-T can remain in contact with the skin over an extended period of time. As a consequence, the action of the active principles can be limited specifically on the injured skin area, reducing the cutaneous irritative effects of DMSO. The following types of semisolid formulations containing 50% m/m DMSO and 2.5% m/m α-T were prepared: hydrophilic ointment, o/w emulsion, hydrophilic gel and lipophilic gel. The ex vivo skin permeation of DMSO and α-T was evaluated by using modified Franz’s diffusion cells and human stratum corneum and epidermis (SCE) as a membrane. The permeated and retained amounts of DMSO and α-T were determined. The oleogel preparation, the hydrophilic gel and the o/w emulsion were uniform in colour and aspect, without any evidences of phase separation over the period of the study. Hydrophilic ointments were discarded as they showed phase separation after 12 h. All formulations had a different behaviour in terms of skin permeability. In particular, hydrogel and o/w emulsion showed the best control on the drug release considering the interactions of the vehicle components with the SCE and the drugs partition between the vehicle and the SCE. The DMSO permeated amount after 24 h was 4.1 mg/cm² for hydrogel and 2.5 mg/cm² for emulsion while the permeated amount of pure DMSO after 24 h was 47.5 mg/cm². Therefore, aiming to reduce side effects after the topical application of the antidotes DMSO and α-T, these results suggested that hydrogel and o/w emulsion could be considered the most promising formulations for further clinical evaluations in managing of extravasation of anthracyclines.     

Diastolic or systolic left and right ventricular impairment at moderate doses of anthracycline?

A prospective study was carried out to assess the early and later alterations in left and right ventricular diastolic and systolic function after the termination of anthracycline therapy. In 33 women without cardiac disease who were treated by anthracycline therapy, cardiac function was evaluated by radionuclide angiography before the treatment (T₀) and 1 month (T₁) and 12 months (T₁₂) after the end of the treatment. Cardiac function was assessed by radionuclide measurement throughout treatment. Analysis of ejection fraction (EF), peak ejection rate (PER), time to PER (TPER), peak filling rate (PFR) and time to PFR (TPFR) was performed before and after treatment. To normalise radionuclide measurements of the ventricular diastolic function, the ratio of the PFR and the EF and the ratio of the PFR and the PER were calculated. No patient developed symptomatic congestive cardiac failure. One-way analysis of variance showed a significant decrease in the three parameters (EF, PER, PFR) over time only for the left ventricle (LV); no significant alterations appeared for the right ventricle (RV). The EF of the LV decreased from 59%±5% at T_o to 57%±6% at T₁ and 56%±5% at T₁₂. The PER of the LV fell from 3.03±0.40 end-diastolic volume per second (EDV/s) at T₀ to 2.79±0.47 at T₁ and 2.78±0.43 at T₁₂. The PFR of the LV dropped from 2.99±0.43 EDV/s at T₀ to 2.62±0.44 at T₁ and 2.56±0.42 at T₁₂. For the normalised ratios, no differences were observed. Significant differences were found for EF, PER and PFR between T₀ and T₁, and between T₀ and T₁₂, but no difference was found between T₁ and T₁₂. This report shows simultaneous impairment of the systolic and diastolic LV radionuclide parameters at 1 and 12 months after anthracycline therapy without alteration in the RV function.     

新的蒽环类抗生素80334B,C和F的研究 Ⅱ.发酵、分离、理化特性、生物学活性和化学结构的测定

襄樊假孢囊放线菌(Actinosporangium xiangfanensis SIPI 80334 nov.sp)产生三个新的蔥环类抗肿瘤抗生素80334 B,C和F。本文报告这三个新抗生素的发酵,分离和精制、理化特性、抗菌和抗肿瘤等生物学活性以及化学结构的测定。     

Geriatric assessment and biomarkers in patients with metastatic breast cancer receiving first-line mono-chemotherapy: Results from the randomized phase III PELICAN trial

Objectives

To determine predictive/prognostic factors for patients with metastatic breast cancer (MBC) receiving first-line monochemotherapy using biomarker analysis and geriatric assessment (GA).

Response to chemotherapy of solitary fibrous tumour: A retrospective study

BackgroundTo report on anthracycline-based chemotherapy in a retrospective case-series analysis of solitary fibrous tumour (SFT) patients treated within the Italian Rare Cancer Network.Patients and methodsWe reviewed a set of SFT treated with chemotherapy since 2002, focusing on anthracycline, administered alone or in combination with ifosfamide. Responses to ifosfamide as a single agent were also evaluated. Pathologic diagnosis was centrally reviewed, distinguishing typical, malignant (MSFT) and dedifferentiated (DSFT) subtypes.ResultsAmong 42 SFT patients treated with chemotherapy, we selected 31 cases (mean age: 62 years; locally advanced/metastatic: 13/18; front-line/further line: 25/6; typical/MSFT/DSFT/not assessable: 1/17/12/1) who received anthracycline-based chemotherapy (anthracycline monotherapy: eight; anthracycline + ifosfamide: 23). 30 patients are evaluable for response. Best response by Response Evaluation Criteria in Solid Tumours (RECIST) was: partial response (PR): 6 (20%), stable disease (SD): eight (27%), progressive disease (PD): 16 (53%) cases. Responses were confirmed after 3 months. Median progression-free survival (PFS) was 4 (range 2–15) months, with 20% of patients being progression-free at 6 months. PR was found in 2/18 (11%) MSFT and 4/12 (30%) DSFT, with a median PFS of 3.5 and 5 months in MSFT and DSFT, respectively. 19 patients received high-dose prolonged-infusion ifosfamide (front-line/further line: 11/8; typical/MSFT/DSFT: 0/15/4) with two (10%) PR, five (26%) SD, 12 (63%) PD.ConclusionsThis retrospective series suggests that in SFT anthracyclines have a degree of antitumour activity in the range of soft tissue sarcoma chemotherapy. Ifosfamide monotherapy seemed to have lower activity. A higher response rate was observed in DSFT in comparison to MSFT. Studies on targeted therapies are ongoing.     

运用心肌综合指数预测蒽环类药物早期心脏毒性的可行性研究

目的通过实时三维斑点追踪成像技术(three-dimensional speckle tracking imaging,3D-STI)获取左心室心肌综合指数(myocardial composite index,MCI),探讨该参数对乳腺癌患者术后蒽环类化学药物治疗所致早期心肌毒性的可行性。方法选取58例欲行6周期蒽环类化学治疗的乳腺癌术后患者进行前瞻性观察,分别获取其化学药物治疗前及化学药物治疗3周期(中期)、化学药物治疗6周期(后期)后24~48 h内的常规及三维超声心动图。通过图像处理及软件分析,得到左心室相关应变及扭转参数,计算左心室心肌综合指数(MCI),比较不同化学药物治疗阶段相关参数的统计学差异,通过受试者工作特征曲线(the receiver operating characteristic curve,ROC)评价左心室相关三维参数诊断心脏早期毒性的可行性;同步监测不同化学药物治疗阶段患者的血清Hs-cTnT浓度,将其与MCI进行相关性分析。结果参照化学药物治疗前,MCI在化学药物治疗3周期时即出现明显减低(P<0.05),其ROC曲线下面积(area under the cure,AUC)为0.925,取截断值为-235.75(%×°),判断蒽环类药物引发心脏毒性的灵敏度为91.4%,特异性为86.2%,均高于其它参数;化学药物治疗完成时,血清Hs-cTnT测值尽管处于正常范围内,但其数值逐步增高,差异有统计学意义;Pearson相关性分析表明,不同化学药物治疗阶段MCI与血清Hs-cTnT浓度呈负相关(化学药物治疗中期,r=-0.595,P<0.05;化学药物治疗后期,r=-0.631,P<0.05)。结论在化学药物治疗进程中,应用3D-STI得到的新参数MCI评估蒽环类药物心脏毒性的灵敏度和特异度均较高,用于临床早期检出蒽环类药物所致乳腺癌患者左心室心肌毒性具有可行性。     

The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review

This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from dexrazoxane. There are also numerous possibilities for dexrazoxane in other clinical situations, which must be addressed in future trials.The authors wrote this article on behalf of an expert panel. The other members of the panel were: S.E. Lipshultz (University of Rochester Medical Center and Golisano Children's Hospital at Strong, Rochester, NY, USA); D. Machover (Dept. Maladies Sanguines et Tumorales, Hôpital Paul-Brousse, Villejuif, France); J. Robert (Institut Bergonié, Bordeaux, France); J.A. Sparano (Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY, USA); J.L. Speyer (New York University School of Medicine, Kaplan Comprehensive Cancer Center, NY, USA); L.H. Wexler (Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY, USA).This article was written in a personal capacity and does not represent the opinions of the National Institutes of Health, the Department of Health and Human Services, or the Federal Government of the United States.     

超声心动图评价蒽环类药对乳腺癌患者心脏毒性

目的探讨背向散射积分(IBS)参数测定技术在评价蒽环类抗肿瘤药(ATC)对乳腺癌患者心脏毒性方面的应用价值.方法应用Philips Sonos-5500型超声诊断仪测定39例接受ATC化疗的乳腺癌患者及29例正常对照组的常规超声心动图心功能参数以及心肌背向散射积分参数:心肌背向散射积分均值(IBS);背向散射积分的心动周期变化幅度(CVIB);心肌校正的背向散射积分均值(IBS%)和背向散射积分周期变异率(CVIB%).结果乳腺癌化疗组IBS的周期性变化幅度明显减低、心肌IBS%较对照组明显增高(P<0.05)、CVIB和CVIB%则较对照组明显减低(P<0.05,P<0.01);乳腺癌化疗组有14例出现左心室舒张功能指标异常;但左心室收缩功能参数在ATC化疗组和对照组之间无显著性差异;IBS参数与ATC累积剂量、距首次化疗时间、心功能参数及相应节段的室壁增厚率均无显著相关性.结论背向散射积分参数测定可作为评价乳腺癌患者应用ATC早期心脏毒性的手段之一.     

右丙亚胺联合参麦注射液在减少急性白血病化疗中心脏毒性的临床研究

目的：观察比较右丙亚胺注射液单用,参麦注射液单用及右丙亚胺参麦注射液联合使用对急性白血病患者化疗期间心脏毒性的影响。方法将2010年1月-2014年6月该院收治的105例已明确诊断为急性白血病的患者随机分为3组,每组35例。每组患者均应用含有蒽环类药物的化疗方案。A组：右丙亚胺组,在应用蒽环类药物化疗前30 min将右丙亚胺注射液快速静脉滴注。 B组：参麦注射液组,对化疗患者给予参麦注射液保护心脏治疗,用法为50 mg/d静脉滴注。 C组：联合用药组,化疗同时联合应用右丙亚胺及参麦注射液保护心脏。每组药物均在化疗期间使用,化疗结束后停止使用。观察并记录3组患者心肌酶数值变化,心电图改变及左心室射血分数的变化。结果比较3组患者化疗前后的心电图变化,心肌酶变化及左心室射血分数变化,观察其心脏损害的程度及比例。结果表明C组患者各种心脏损害的指标均低于A,B两组。结论右丙亚胺及参麦注射液联合应用对于接受以蒽环类药物为基础的化疗方案的患者,可明显减轻其心脏毒性作用,可作为降低蒽环类药物心脏毒性的新途径。