Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone

Dexrazoxane has been reported to be protective against anthracycline induced subcutaneous ulceration in mice. It is currently under clinical investigation as an acute antidote in accidental anthracycline extravasation, for which indication topical dimethylsulfoxide (DMSO) and intralesional hydrocortisone are used empirically. We studied the effect in 72 mice of monotherapy with and combined therapy of intraperitoneal dexrazoxane, topical DMSO, and intralesional hydrocortisone as acute antidotes against ulceration after subcutaneous daunorubicin. Dexrazoxane completely prevented wounds from occurring, while neither DMSO nor hydrocortisone had any preventive effect. The addition of topical DMSO actually reduced the efficacy of dexrazoxane. In conclusion, the present study does not support the concomitant use of topical DMSO + systemic dexrazoxane or intralesional hydrocortisone + systemic dexrazoxane. Monotherapy with systemic dexrazoxane seems preferable and is highly efficacious in preventing ulceration.     

蒽环类化疗药物外渗漏的治疗进展

蒽环类化疗药物是一种常用的抗肿瘤药物，在静脉给药过程中如果发生外渗可导致严重化疗并发症，本文阐述了蒽环类化疗药物外渗的机制、原因、临床表现及诊疗，重点介绍蒽环类化疗药物外渗漏的相关治疗的研究进展，包括针对蒽环类药物外渗漏解毒剂的介绍，并讨论了治疗过程中存在的一些争议性的问题。     

Phase II study of dose-dense doxorubicin and docetaxel as neoadjuvant chemotherapy with G-CSF support in patients with large or locally advanced breast cancer

Introduction  To evaluate the efficacy and safety profile of the concomitant dose-dense administration of doxorubicin and docetaxel as primary chemotherapy for patients with large or locally advanced breast cancer. Materials and methods  Forty-seven patients were included and received 50 mg/m² of doxorubicin and 75 mg/m² of docetaxel every two weeks for four cycles. Primary prophylaxis with granulocyte colony stimulating factor was administered. Results  Patients included had mainly stage III disease (66%). Efficacy and toxicity analyses were carried out on an intention-to-treat basis. After study treatment, the rate of clinical responses was 85% (95% CI: 75–95) with 6% judged as clinical complete responses. Surgery was performed on 94% patients for whom the breast was conserved in 27%. Only one patient obtained a pathological complete response (with no evidence of invasive or non-invasive tumour in the breast and the lymph nodes). In three additional patients, malignant cells were detected only in one lymph node. The single severe haematological toxicity was neutropenia, occurring in one patient (2%) and two cycles (1%), being grade 3 in one and grade 4 in the other. Severe non-haematological toxicities were grade 3, and the most common was asthenia (8% of patients), followed by cutaneous toxicity, arthromyalgia and stomatitis, which occurred in fewer than 4% of patients in each case. Conclusions  The concomitant dose-dense administration of doxorubicin and docetaxel as neoadjuvant chemotherapy with granulocyte colony stimulating factor support is a feasible and effective schedule with a safe toxicity profile for women with large or locally advanced breast cancer.     

Anthracycline cardiomyopathy

Summary Life-threatening irreversible cardiomyopathy is a major complication of anthracycline therapy, particularly in the pediatric population. The pediatric cardiologist, in concert with the primary oncologist, should therefore play a major role in the care of patients receiving these agents and in clinical trials involving their use. Many risk factors and their relationships to drug pharmacokinetics, mechanisms of action, and toxicity have been identified. These data provide a rational basis for present-day recommendations regarding anthracycline administration and dosage scheduling. They furthermore provide potential avenues for clinical investigation aimed at improving the therapeutic index of these agents: -tocopherol, cytochrome Q₁₀, and other free radical scavengers may decrease the deleterious effects of free radical generation on the myocardium without apparent interference with tumoricidal effect. The cardiac glycosides may decrease cardiac toxicity by specific myocardial exclusion. Anthracycline analogs have been designed to specifically inhibit myocardial binding and/or free radical generation. Clinical trials involving these agents are difficult to interpret because of variability in front end risk factors and dosage schedules in the study population. Furthermore, the relatively low (5 to 10%) incidence of affected patients implies the need for large numbers to demonstrate a statistically significant benefit. Pediatric protocols addressing these issues are urgently needed. Guidelines for present-day management and future studies are outlined.Supported in part by Hematology Research Training Grant 2T32-HL07145-06A1 and USPH Grant CA 07306. This paper was part of the Ray C. Anderson Symposium     

Bleomycin,epidoxorubicin, cyclophosphamide,vincristine and prednisone (BACOP) in patients with follicular non-Hodgkin's lymphoma: results of a prospective,multicenter study of the Gruppo Italiano Per Lo Studio Dei Linfomi (GISL)

At present we report the results of a prospective, non-randomized open trial, conducted on follicular lymphoma (FL) patients by the Gruppo Italiano per lo Studio dei Linfomi (GISL), after a median follow-up of 62.6 months. Seventy-three patients with FL were registered to the study and treated with combination chemotherapy consisting of cyclophosphamide, epidoxorubicin, vincristine, bleomycin and prednisone, weekly administered every 4 weeks. After chemotherapy, involved-field radiotherapy was delivered in case of either localized, bulky and extranodal disease at presentation or limited residual disease at the end of chemotherapy. Patient received four or eight chemotherapy courses in case of localized or advanced disease, respectively. The overall response rate at the end of the treatment program was 97.3%, with 78.1% CR and 19.2% PR. CR rate was 94.3 and 63.1% in stage I-II and III-IV, respectively ( p =0.006). Beside the stage, response rate was significantly influenced by bone marrow involvement, and the number of extranodal sites. Relapse free survival was 60.8% at 5 years in the whole series; in localized disease it was 70.3 vs. 44.8% in advanced disease ( p =0.044) . Relapse free survival was significantly influenced by stage, bone marrow involvement, number of extranodal sites and International Prognostic Index (IPI) score. The overall 5-year survival rate was 90.2%; being 95.6% for patients with stage I-II and 85.1% for those III-IV ( p =0,0133). In addition, both IPI and Italian Lymphoma Intergroup (ILI) score had a significant impact on survival. The toxicity profile of the treatment was acceptable. From the results of this prospective study it is possible to conclude that this regimen and the whole treatment program is effective as first line therapy for the general population of FL. In particular the BACOP schedule is a valid anthracycline-containing regimen, and in this respect suitable to be considered as a treatment option.     

High efficacy of gemcitabine and cisplatin plus trastuzumab in patients with HER2-overexpressing metastatic breast cancer: a phase II study

AimsEffective and tolerable regimens are sought specifically in women who have been pre-treated with anthracyclines and taxanes. Gemcitabine and cisplatin plus trastuzumab has shown synergistic activity in vitro, and provides a new mechanism of drug interaction. This multicentre phase II study aimed to evaluate the efficacy and tolerability of gemcitabine and cisplatin plus trastuzumab in previously treated patients with metastatic breast cancer (MBC).Materials and methodsPreviously treated patients with human epidermal growth factor receptor 2 (HER2) overexpressing MBC were enrolled in a multicentre phase II study (DAKO Hercep Test 3+). Treatment consisted of gemcitabine (750 mg/m²), cisplatin (30 mg/m²) given on days 1 and 8 every 3 weeks, and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly).ResultsTwenty patients were recruited, all of whom had previously received chemotherapy (12 pre-treated with taxanes, 18 pre-treated with anthracyclines seven pre-treated with taxanes and trastuzumab). A median of six cycles of the study treatment was delivered. There were eight partial responses, for an overall response rate of 40% (95% confidence interval 16.5–63.5%). The clinical benefit rate (complete response plus partial response plus stable disease) was 80% (95% CI 54.2–95.8%). The response rate in patients who had already received a trastuzumab-based regimen for MBC was 57.1% (95% CI 7.7–100%). Median time to progression was 10.2 months, and median overall survival was 18.8 months. Main toxicities were leukopenia (grade 3 in 55% of patients) and thrombocytopenia (grade 3 in 35% and grade 4 in 5% of patients). Non-haematological toxicity was rarely severe.ConclusionsCombination chemotherapy with gemcitabine and cisplatin plus trastuzumab is well tolerated and active in patients with HER2 overexpressing MBC, even after prior exposure to anthracyclines and taxanes.     

5′-deoxy-5-fluorouridine, medroxyprogestrone acetate and mitoxantrone hydrochloride for advanced or recurrent Breast Cancer

BACKGROUND: In treating advanced or recurrent breast cancer, anthracycline-containing chemotherapy is used for palliation and to maintain quality of life. However, there are several drawbacks including therapeutic failure and cardiotoxicity. We evaluated the efficacy and toxicity of combination chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR), medroxyprogestrone acetate (MPA) and mitoxantrone hydrochloride (MIT). METHODS: Sixteen patients with advanced or recurrent breast cancer were enrolled. Chemotherapy was given in a 28-day cycle, starting with MIT 10 mg/m2 intravenously on day 1, then oral 5'-DFUR 800 mg and MPA 800 mg daily. Two or more cycles were given. RESULTS: Fifteen patients were assessable for response and toxicity. Thirteen patients had been treated previously with an anthracycline containing regimen and 2 with CMF. There were 2 partial response patients (13.3%) and 1 complete response patient (6.7%). There were 11 patients showing no change (NC) (73.3%), one of whom was a minor responder and 7 with a long period of NC. There was only one with progressive disease patient. The overall response rate was 20.0%. Adverse events occurred in 5 patients (33.3%). Myelosuppression was the most common with 5 patients becoming leukopenic (33.3%). Nausea/vomiting was the second most common side effect, affecting 2 patients (13.3%). CONCLUSION: Given its high efficacy and preservation of QOL, the combination of MIT, 5'-DFUR and MPA can be a 2nd or 3rd line therapy for advanced or recurrent breast cancer, especially for anthracycline-resistant cases.     

中药汤剂治疗蒽环类药物所致心脏毒性的网状Meta分析＊

目的 系统评价中药汤剂在伴有蒽环类药物的治疗效果下对心脏毒性的防治效果。方法 计算机检索PubMed、ELSEVIER、The Cochrane Library、Web of Science、CNKI和WanFang Date等数据库查找中药汤剂治疗蒽环类药物所致心脏毒性的对照案例数据并核对文献共纳入文献28篇，对照措施为西药对照或空白对照。采集文献中的数据利用Stata、Winbugs、R软件进行Meta分析。文献中的数据信息统一单位，由2位研究员经过筛选后除去数据不太清楚的文献和使用中药注射液，中成药的文献。结果 Meta分析结果显示在LVEF方面，红景天汤剂具有最佳疗效。在CK-MB方面，当归养心汤具有最佳疗效。在CTNI方面，炙甘草汤最优。在心电图方面，益气养心汤最优。结论 综合各个指标的结果，生脉汤剂，益气养心汤，参芪仙补汤，红景天汤剂是较优疗效的中药汤剂，在对肿瘤蒽环类化疗导致心脏毒性方面具有保护作用并减轻心脏损伤。     

Role of P53 and BCL-2 in high-risk breast cancer patients treated with adjuvant anthracycline-based chemotherapy

Purpose: Adjuvant therapy has become an integral component of the management of primary high-risk breast cancer patients. However, a considerable fraction of women receive no benefit from this treatment. This study investigates whether a number of biopathological factors can influence the outcome of patients submitted to adjuvant chemotherapy involving the use of high-dose epirubicin and cyclophosphamide. Methods: One hundred and fifty-seven primary breast cancer patients, considered at high risk according to the St. Gallen Meeting Consensus Conference, were evaluated immunohistochemically for estrogen, progesterone receptors, p53, bcl-2, HER-2/neu, and Ki-67, of which the results were correlated with patient outcome. Results: Results obtained demonstrated that p53 is a significant predictor of disease-free survival (DFS P < 0.0001) and overall survival (OS P=0.0002) both in ductal and lobular carcinomas, whereas bcl-2 expression seems to be of prognostic value only in lobular carcinomas (DFS P=0.01; OS P=0.02). Conclusions: This data indicates that in high-risk breast cancer patients the immunohistochemical evaluation of p53 and bcl-2 may be of clinical value in distinguishing different responses to adjuvant anthracycline-based chemotherapy. Received: 4 October 1999 / Accepted: 10 April 2000     

A phase II trial of docetaxel (Taxotere<Superscript>®</Superscript>) as second-line chemotherapy in patients with metastatic breast cancer

The efficacy and tolerability of docetaxel 100 mg/m2 every 3 weeks as second-line chemotherapy in patients with metastatic breast cancer was investigated. In addition, the efficacy of a 3-day prophylaxis against cumulative dose-related fluid retention was examined with methylprednisolone 32 mg twice daily for 3 days starting 12 and 3 h before the docetaxel infusion together with oral cetirizine 10 mg 12 and 3 h before start of docetaxel for prevention of acute hypersensitivity reactions. According to the intent to treat-analysis 35% (95%CI: 25; 46) of the 94 patients entered responded to therapy. Their median survival was 12 months (range 0–20 months). The respective response rate for the 87 patients eligible for response evaluation was 37% (95%CI: 27; 48). Their median duration of response was 8 months (range 3–12 months), their median time to progression was 4 months (range 1–12 months). The corresponding response rate in the eligible patient cohort with anthracycline-resistant disease was 28% (95%CI: 15; 45) and increased to 44% (95%CI: 30; 59) in the cohort with non-anthracycline-resistant disease. Patients with visceral metastases responded in 36% and patients with ≥3 organs involved in 33%. In a retrospective analysis, the 3-day premedication of corticosteroids and antihistamines proved to be as effective as the established but more toxic 5-day regimen in delaying and preventing the occurrence of docetaxel derived toxicities especially the cumulative fluid retention. In conclusion, docetaxel represents one of the most active agents for second-line treatment of metastatic breast cancer, especially for anthracycline-resistant patients. Due to comparable effectiveness of the 5-day regimen which is widely used by others and the 3-day premedication tested in this trial the latter proved to be more favourable and was therefore recommended for future therapies.