Capri G, Tarenzi E, Fulfaro F, Gianni L
Division of Medical Oncology, Istituto Nazionale Tumori, Milano, Italy.
Semin Oncol. 1996 Feb;23(1 Suppl 2):68-75.
The taxanes paclitaxel and docetaxel are undergoing extensive evaluation in women with breast cancer in the United States and in Europe. Their dose-limiting toxicity is neutropenia. Paclitaxel also causes peripheral neuropathy, while docetaxel can cause unpredictable and severe skin toxicity, as well as edema and effusions due to a capillary leak syndrome. Due to threshold pharmacodynamics and nonlinear pharmacokinetics, tolerability of paclitaxel is schedule dependent. Single-agent paclitaxel was very active in multiple phase II trials in patients with different numbers and types of prior chemotherapy and disease extent (20% to 60% complete plus partial responses). Effective doses ranged from 135 to 250 mg/m2. Activity was observed with all infusion schedules (1, 3, and 24 hours) and in women with anthracycline-resistant tumors (25% to 38%). The use of a 96-hour infusion schedule was very active in anthracycline-refractory patients (48%) and in women who failed short infusion taxanes. The drug is undergoing extensive evaluation in combination with doxorubicin, cyclophosphamide, cisplatin, and antimetabolites. Very promising efficacy was observed for paclitaxel by 3-hour infusion plus bolus doxorubicin (approximately 40% complete responses and 50% partial responses). The combination also caused a high incidence of clinically reversible congestive heart failure(14% to 18%). Docetaxel also has very good efficacy in breast cancer, with approximately 70% major responses in untreated patients and more than 50% in anthracycline-resistant tumors. There is no evidence that efficacy and tolerability are schedule dependent as is the case for paclitaxel. At recommended doses (100 or 75 mg/m2 by 1-hour infusion every 3 weeks), docetaxel causes a fluid retention syndrome that may affect quality of life. Its common onset after multiple cycles may limit the use of docetaxel for palliation in metastatic breast cancer. These results clearly indicate that the taxanes will become a standard component of initial chemotherapy for women with breast cancer. The definition of their actual role still requires an answer to the unresolved questions of their optimal dose and combination with other anticancer agents. Most importantly, the drugs should be prospectively evaluated in a randomized study using comparable doses and schedules to assess which of the two has the better therapeutic index in breast cancer.
紫杉烷类药物紫杉醇和多西他赛正在美国和欧洲的乳腺癌女性患者中接受广泛评估。它们的剂量限制性毒性是中性粒细胞减少。紫杉醇还会引起周围神经病变，而多西他赛可导致不可预测的严重皮肤毒性，以及因毛细血管渗漏综合征引起的水肿和积液。由于阈值药效学和非线性药代动力学，紫杉醇的耐受性取决于给药方案。单药紫杉醇在针对不同化疗次数、化疗类型及疾病程度的患者进行的多项II期试验中活性很高（完全缓解加部分缓解率为20%至60%）。有效剂量范围为135至250mg/m²。在所有输注方案（1小时、3小时和24小时）中以及在对蒽环类耐药的肿瘤女性患者中均观察到活性（25%至38%）。96小时输注方案在蒽环类难治性患者（48%）以及对短时间输注紫杉烷类药物治疗无效的女性患者中活性很高。该药物正在与多柔比星、环磷酰胺、顺铂和抗代谢药物联合使用方面接受广泛评估。通过3小时输注加推注多柔比星使用紫杉醇观察到非常有前景的疗效（约40%完全缓解和50%部分缓解）。该联合用药还导致临床可逆转的充血性心力衰竭发生率很高（14%至18%）。多西他赛在乳腺癌中也具有很好的疗效，在未经治疗的患者中约70%有主要缓解，在对蒽环类耐药的肿瘤患者中超过50%有主要缓解。没有证据表明其疗效和耐受性像紫杉醇那样取决于给药方案。按照推荐剂量（每3周1小时输注100或75mg/m²），多西他赛会引起液体潴留综合征，这可能会影响生活质量。其在多个周期后常见的发作可能会限制多西他赛在转移性乳腺癌姑息治疗中的应用。这些结果清楚地表明，紫杉烷类药物将成为乳腺癌女性患者初始化疗的标准组成部分。它们实际作用的界定仍需要回答关于其最佳剂量以及与其他抗癌药物联合使用的未解决问题。最重要的是，应在一项随机研究中对这些药物进行前瞻性评估，使用可比的剂量和方案来评估两者中哪一种在乳腺癌中具有更好的治疗指数。
