Phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer: a West Japan Thoracic Oncology Group (WJTOG) study

Summary Purpose: We conducted a multicenter phase II study of amrubicin, a novel 9-aminoanthracycline, to evaluate its efficacy and safety in patients with non-small-cell lung cancer (NSCLC). Patients and methods: Entry requirements included cytologically or histologically proven measurable NSCLC, stage III or IV, no prior therapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and adequate organ function. Amrubicin was given by daily intravenous injection at 45 mg/m²/day for three consecutive days, repeated at 3 week intervals. Each patient received at least three treatment cycles. Results: Sixty-two patients were enrolled in this study. Of the 62 registered patients, 60 were eligible and assessable for efficacy, and 59 for toxicity. Overall response rate was 18.3% (95% confidence interval [CI], 9.5 to 30.4%) and median survival time was 8.2 months (95% CI, 6.7 to 10.4 months). Major toxicity was myelosuppression, with incidences of grade 3 or 4 toxicity of 78.0% for neutropenia, 54.2% for leukopenia, 30.5% for anemia, and 28.8% for thrombocytopenia. Non-hematological toxicities with a greater than 50% incidence were anorexia (69.5%), nausea/vomiting (55.9%), and alopecia (75.9%), but were relatively mild, with grade 3 toxicities observed in only one patient each (1.7%). Conclusion: Amrubicin was an active, well-tolerated agent in the treatment of NSCLC.     

Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: Comparative studies against doxorubicin and mitoxantrone

Anthracyclines and anthracenediones are important oncotherapeutics; however, their use is associated with irreversible and cumulative cardiotoxicity. A novel aza-anthracenedione, pixantrone (BBR 2778), was developed to reduce treatment-related cardiotoxicity while retaining efficacy. This study evaluates the cumulative cardiotoxic potential of pixantrone compared with equiactive doses of doxorubicin and mitoxantrone in both doxorubicin-pretreated and doxorubicin-na?ve mice. CD1 female mice were given doxorubicin 7.5 mg/kg (once weekly for 3 weeks) followed 6 weeks later by either sterile 0.9% saline, doxorubicin 7.5 mg/kg, pixantrone 27 mg/kg, or mitoxantrone 3 mg/kg (once weekly for 3 weeks). A second group of CD1 female mice were given 2 cycles of either sterile 0.9% saline, pixantrone 27 mg/kg, doxorubicin 7.5 mg/kg, or mitoxantrone 3 mg/kg (once weekly for 3 weeks). Animals were sacrificed at different time points for histopathologic examination of the heart. In the doxorubicin-pretreated mice, further exposure to doxorubicin or mitoxantrone resulted in a significant worsening of pre-existing degenerative cardiomyopathy. In contrast, pixantrone did not worsen pre-existing cardiomyopathy in these animals. Only minimal cardiac changes were observed in mice given repeated cycles of pixantrone, while 2 cycles of doxorubicin or mitoxantrone resulted in marked or severe degenerative cardiomyopathy. These animal studies demonstrate the reduced cardiotoxic potential of pixantrone compared with doxorubicin and mitoxantrone. Exposure to pixantrone did not worsen pre-existing cardiomyopathy in doxorubicin-pretreated mice, suggesting that pixantrone may be useful in patients pretreated with anthracyclines.     

Amrubicin for non-small-cell lung cancer and small-cell lung cancer

Summary Amrubicin is a totally synthetic anthracycline anticancer drug and a potent topoisomerase II inhibitor. Recently, amrubicin was approved in Japan for the treatment of small- and non-small-cell lung cancers (SCLC and NSCLC). Here, we review the efficacy and toxicities of amrubicin monotherapy and amrubicin in combination with cisplatin for extensive-disease SCLC (ED-SCLC), and of amrubicin monotherapy for advanced NSCLC, as observed in the clinical trials. Recommended dosage for previously untreated advanced NCSLC was 45 mg/m²/day by intravenous administration for 3 days. Dose-limiting toxicities were leucopenia, thrombocytopenia, and gastrointestinal disturbance. Response rate was 27.9% for advanced NSCLC, and 75.8% for ED-SCLC with a median survival time (MST) of 11.7 months. Recommended dosage of amrubicin was 40 mg/m²/day in combination with cisplatin at 60 mg/m²/day, with MST of 13.6 months and 1-year survival rate of 56.1%. In sensitive or refractory relapsed SCLC, response rate was 52 and 50%, progression-free survival was 4.2 and 2.6 months, overall survival was 11.6 and 10.3 months, and 1-year survival rate was 46 and 40%, respectively. These results are promising for the treatment of both NSCLC and SCLC. Further clinical trials will clarify the status of amrubicin in the treatment of lung cancer.     

Phase II study of amrubicin in previously untreated patients with extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) study

Summary Purpose: To evaluate the efficacy and safety of amrubicin, (+)-(7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl )oxy ]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride, in previously untreated patients with extensive-disease small cell lung cancer (SCLC). Patients and methods: A total of 35 previously untreated patients with extensive-disease SCLC were entered into the study. Amrubicin was given by daily intravenous infusion at 45 mg/m²/day for 3 consecutive days, every 3 weeks. Unless there was tumor regression of 25% or greater after the first cycle, or 50% or greater after the second cycle, treatment was switched to salvage chemotherapy in combination with etoposide (100 mg/m², days 1, 2, and 3) and cisplatin (80 mg/m², day 1). Results: Of the 35 patients entered, 33 were eligible and assessable for efficacy and toxicity. Of the 33 patients, 3 (9.1%) had a complete response (95% confidence interval [CI], 1.9–24.3%) and 22 had a partial response, for an overall response rate of 75.8% (95% CI, 57.7–88.9%). Median survival time was 11.7 months (95% CI, 9.9–15.3 months), and 1-year and 2-year survival rates were 48.5% and 20.2%, respectively. The most common toxicity was hematologic. Non-hematologic toxicity of grade 3 or 4 was only seen in 3 patients with anorexia (9.1%) and 1 patient with alopecia (3.0%). Salvage chemotherapy was administered to only 6 patients. Conclusion: Amrubicin was active for extensive-disease SCLC with acceptable toxicity. Further studies in combination with other agents for SCLC are warranted.     

蒽环类抗肿瘤抗生素的研究进展

蒽环类抗生素是目前临床上广泛使用的一类有效的化疗药物。本文从临床应用、作用机制、不良反应以及新剂型的开发等方面阐述了蒽环类抗生素的研究近况。     

缺血修饰清蛋白评价蒽环类药物致心肌损伤的临床分析

目的通过检测应用不同累积剂量蒽环类(anthracycline,ANT)药物化疗前后血液系统恶性肿瘤患者血清中缺血修饰清蛋白(ischemia-modified albumin,IMA)及心肌肌钙蛋白I(cardiac troponin I,cTnI)水平的变化,探讨IMA在评价ANT化疗药物引起患者心肌损伤的敏感程度中的作用。方法选取90例血液系统恶性肿瘤患者,根据蒽环类药物的累积剂量将其分为3组:A组(未化疗组);B组(0～450 mg/m2组);C组(450～800 mg/m2组);用清蛋白钴结合(albu-min cobalt binding,ACB)试验测定患者用药后IMA水平,应用日本Olympus公司的AU2700全自动生化分析仪检测cTnI水平。结果应用ANT化疗药物的患者IMA水平较未化疗组明显升高(P<0.01),应用高剂量ANT化疗药物(450～800mg/m2)的患者较应用低剂量ANT化疗药物(0～450 mg/m2)患者IMA水平明显升高(P<0.01)。结论 IMA可能是ANT化疗药物所致早期心肌损伤新的血清学标志物。     

Selective axonal transport of anthracycline antibiotics

The retrograde intraaxonal transport of several anthracycline antibiotics was assessed in the peripheral nervous system of adult mice. Despite certain chemical similarities, the intraaxonal transport of these molecules was variable and could be correlated with the structure of the aminosugar at the R-2 position. One particularly interesting compound, 4′-deoxydoxorubicin, was transported by dorsal root ganglia axons, but not by the axons of ventral horn neurons. These observations suggest that the sugar component of a molecule may be important for its intraaxonal transport in the peripheral nervous system.     

Tei指数监测蒽环类药物对肿瘤患者左心功能的影响

目的探讨心肌做功指数（myocardial performance index,MPI又称Tel index）在评价蒽环类药物（anthracycline,ATC）对肿瘤患者左心功能早期损害方面的临床应用价值。方法测定并比较50例肿瘤患者ATC化疗前和化疗后6个月常规超声心动图参数及Tei指数的变化。结果与化疗前相比,左心室等容舒张时间（IRT）延长（P〈0．05）,左心室Tei指数明显升高（P〈0．01）。而左心内径及收缩功能指标（EF、FS）化疗前后无显著性差异,仅14例（28％）患者化疗后出现一项或多项常规左室舒张功能指标异常（E峰减低,A峰升高,E／A〈1）。结论Tei指数能更早、更敏感地评价ATC对肿瘤患者左心功能的损害。     

超声心动图检测蒽环类抗肿瘤药心脏毒性

蒽环类抗肿瘤药可引起心脏毒性已众所周知，但由于其广谱有效的化疗效果使其成为肿瘤化疗中不可或缺的药物之一。因此早期心脏毒性的检测对于及时预防或治疗迟发性心脏损害甚为重要。随着医疗技术的发展，相应检测方法不断发展完善，常规超声心动图结合超声心动图新技术是其中颇有价值的方法之一。