O'Shaughnessy J A, Cowan K H
Medical Breast Cancer Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Breast Cancer Res Treat. 1995;33(1):27-37. doi: 10.1007/BF00666068.
Paclitaxel is a highly active single agent as therapy for previously untreated as well as doxorubicin-refractory metastatic breast cancer, with associated response rates of 62% and 20-48%, respectively. Complete responses with paclitaxel occur chiefly in breast cancer patients whose metastatic disease has not been previously treated with chemotherapy. Early data suggest a possible dose-response relationship for paclitaxel in metastatic breast cancer, but the optimal dose has not yet been defined. The optimal duration of infusional paclitaxel treatment is also not yet known. A study of 96-hour infusional paclitaxel in the treatment of doxorubicin- or mitoxantrone-refractory metastatic breast cancer patients has demonstrated a 48% response rate suggesting that prolonged exposures to paclitaxel may offer a therapeutic advantage. Randomized trials of 3- vs 96-hour paclitaxel are ongoing or planned. The relative efficacy of paclitaxel versus standard chemotherapy as front-line or salvage therapy for metastatic breast cancer is currently under study. In addition, two randomized trials are under way in node positive breast cancer patients to study whether treatment with paclitaxel following standard or high dose doxorubicin and cyclophosphamide adjuvant therapy results in improved patient benefit. Combining paclitaxel with other active agents in the treatment of metastatic breast cancer is an area of active investigation. Combined paclitaxel and doxorubicin, administered concurrently or sequentially, is associated with modest complete response rates in metastatic breast cancer patients. Sequential paclitaxel-->doxorubicin administration is associated with more mucositis than is doxorubicin-->paclitaxel when paclitaxel is administered over 24 hours. High doses of cyclophosphamide can be combined with 24- or 72-hour infusional paclitaxel, and phase II studies of this combination are warranted. Early data suggest that administering biweekly paclitaxel and cisplatin to previously untreated metastatic breast cancer patients is associated with high response rates, and confirmatory studies of this combination and schedule are planned. Preclinical data suggest that cell cycle considerations may be important in combining doxorubicin and possibly other agents with paclitaxel. Paclitaxel is an excellent substrate for P-glycoprotein, the protein product of the multidrug resistance-1 (mdr-1) gene, and phase I trials are under way combining paclitaxel with several known blockers of Pgp function. Finally, pilot studies are under way to determine whether the radiation sensitizing effects of paclitaxel can be exploited as part of radiation therapy for patients with locally advanced breast cancer.
紫杉醇作为一种高效的单一药物，可用于治疗既往未接受过治疗以及对多柔比星耐药的转移性乳腺癌，其有效率分别为62%和20 - 48%。紫杉醇治疗产生的完全缓解主要发生在转移性疾病此前未接受过化疗的乳腺癌患者中。早期数据表明，转移性乳腺癌中紫杉醇可能存在剂量反应关系，但最佳剂量尚未确定。紫杉醇输注治疗的最佳持续时间也尚不清楚。一项针对多柔比星或米托蒽醌耐药的转移性乳腺癌患者进行的96小时紫杉醇输注治疗研究显示，有效率为48%，这表明延长紫杉醇暴露时间可能具有治疗优势。3小时与96小时紫杉醇的随机试验正在进行或已计划开展。目前正在研究紫杉醇与标准化疗相比作为转移性乳腺癌一线或挽救治疗的相对疗效。此外，两项针对淋巴结阳性乳腺癌患者的随机试验正在进行，以研究在标准或高剂量多柔比星及环磷酰胺辅助治疗后使用紫杉醇治疗是否能使患者获益更多。在转移性乳腺癌治疗中，将紫杉醇与其他活性药物联合使用是一个积极研究的领域。同时或序贯给予紫杉醇和多柔比星，转移性乳腺癌患者的完全缓解率适中。当紫杉醇在24小时内给药时，序贯给予紫杉醇→多柔比星比多柔比星→紫杉醇会出现更多的黏膜炎。高剂量环磷酰胺可与24小时或72小时输注的紫杉醇联合使用，有必要对这种联合方案进行II期研究。早期数据表明，对既往未接受过治疗的转移性乳腺癌患者每两周给予紫杉醇和顺铂，有效率较高，目前正在计划对这种联合方案和给药方案进行验证性研究。临床前数据表明，在将多柔比星以及可能的其他药物与紫杉醇联合使用时，细胞周期因素可能很重要。紫杉醇是多药耐药-1（mdr-1）基因的蛋白产物P-糖蛋白的良好底物，目前正在进行将紫杉醇与几种已知的Pgp功能阻滞剂联合使用的I期试验。最后，正在进行初步研究，以确定紫杉醇的放射增敏作用是否可作为局部晚期乳腺癌患者放射治疗的一部分加以利用。
